Certain Substituted Amides, Method of Making, and Method of Use Thereof

ABSTRACT

Compounds of Formula I that inhibit Btk are described herein. Pharmaceutical compositions comprising at least one compound of Formula I, together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients, are described. Methods of treating patients suffering from certain diseases responsive to inhibition of Btk activity and/or B-cell activity are described. Methods for determining the presence of Btk in a sample are described.

This application claims priority under 35 U.S.C. §119(e), U.S.Provisional Application No. 60/973,995 filed Sep. 20, 2007, and U.S.Provisional Application No. 61/050,777 filed May 6, 2008, which areincorporated herein by reference.

Provided herein are certain substituted amides and related compounds,compositions comprising such compounds, and methods of their use.

Protein kinases, the largest family of human enzymes, encompass wellover 500 proteins. Bruton's Tyrosine Kinase (Btk) is a member of the Tecfamily of tyrosine kinases, and is a regulator of early B-celldevelopment as well as mature B-cell activation, signaling, andsurvival.

B-cell signaling through the B-cell receptor (BCR) can lead to a widerange of biological outputs, which in tarn depend on the developmentalstage of the B-cell. The magnitude and duration of BCR signals must beprecisely regulated: Aberrant BCR-mediated signaling can causedisregulated B-cell activation and/or the formation of pathogenicauto-antibodies leading to multiple autoimmune and/or inflammatorydiseases. Mutation of Btk in humans results in X-linkedagammaglobulinaemia (XLA). This disease is associated with the Unpairedmaturation of B-cells, diminished immunoglobulin production, compromisedT-cell-independent immune responses and marked attenuation of thesustained calcium sign upon BCR stimulation.

Evidence for the role of Btk in allergic disorders and/or autoimmunedisease and/or inflammatory disease has been established inBtk-deficient mouse models. For example, in standard murine preclinicalmodels of systemic lupus erythematosus (SLE), Btk deficiency has beenshown to result in a marked amelioration of disease progression.Moreover, Btk deficient mice can also be resistant to developingcollagen-induced arthritis and can be less susceptible toStaphylococcus-induced arthritis.

A large body of evidence supports the role of B-cells and the humoralimmune system in the pathogenesis of autoimmune and/or inflammatorydiseases. Protein-based therapeutics (such as Rituxan) developed todeplete B-cells, represent an approach to the treatment of a number ofautoimmune and/or inflammatory diseases. Because of Btk's role in B-cellactivation, inhibitors of Btk can be useful as inhibitors of B-cellmediated pathogenic activity (such as autoantibody production).

Btk is also expressed in osteoclasts, mast cells and monocytes and hasbeen shown to be important for the function of these cells. For example,Btk deficiency in mice is associated with impaired IgE-mediated mastcell activation (marked diminution of TNF-alpha and other inflammatorycytokine release), and Btk deficiency in humans is associated withgreatly reduced TNF-alpha production by activated monocytes.

Thus, inhibition of Btk activity can be useful for the treatment ofallergic disorders and/or autoimmune and/or inflammatory diseases suchas: SLE, rheumatoid arthritis, multiple vasculitides, idiopathicthrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis,and asthma. In addition, Btk has been reported to play a role inapoptosis; thus, inhibition of Btk activity can be useful for cancer, aswell as the treatment of B-cell lymphoma and leukemia. Moreover, giventhe role of Btk in osteoclast function, the inhibition of Btk activitycan be useful for the treatment of bone disorders such as osteoporosis.

Provided is a compound of Formula I:

and pharmaceutically acceptable salts, solvates, and mixtures thereof,wherein

-   X is chosen from N and CR²;-   Y is chosen from N and CR^(3′);-   Z is chosen from N and CR³; provided that only one of X, Y and Z is    N at a time;-   W is chosen from N and CH;-   V is chosen from CH and N; provided that one of W and V must be N    and W and V are not both N;-   R¹ is chosen from:

-   R² is chosen from H, CH₃, F, Cl, CN, OCH₃, OH and CF₃;-   R^(2′) is chosen from H and F;-   R³ is chosen from H, CH₃, CF₃, F, Cl, CN and OCH₃;-   R^(3′) is chosen from H, CH₃, F, Cl, CN and OCH₃;-   R⁴ is

-   m is chosen from 0 and 1;-   n is chosen from 0 and 1;-   R⁵ is chosen from H, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl, wherein said    alkyl is optionally substituted with one or more substituents chosen    from OH, F, and OCH₃;-   R⁶ is chosen from H and C₁-C₆ alkyl; or R⁵ and R⁶ are optionally    taken together with the nitrogen atom to which they are attached to    form a 4- to 6-membered cyclic ring having 0-1 additional N, S or O,    wherein the optional additional ring nitrogen is optionally    substituted with C₁-C₃ alkyl and said cyclic ring is optionally    substituted with OH;-   R⁷ is chosen from H, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl, wherein said    alkyl is optionally substituted with one or more substituents chosen    from OH and O(C₁-C₄ alkyl); or R⁶ and R⁷ are optionally taken    together with the —N(R⁵)C(R⁹)(CH₂)_(n)C(═O)N(R⁸)— group through the    respective nitrogen atoms to which they are directly attached to    form a 6-membered cyclic ring;-   R⁸ is chosen from H and C₁-C₆ alkyl, wherein said alkyl is    optionally substituted with one or more substituents chosen from OH,    F, and OCH₃; or R⁷ and R⁸ are optionally taken together with the    nitrogen atom to which they are attached to form a 4- to 6-membered    cyclic ring having 0-1 additional N, S or O, wherein the optional    additional ring nitrogen is optionally substituted with C₁-C₃ alkyl    and said cyclic ring is optionally substituted with OH;-   R⁹ is chosen from H and CH₃;-   R¹⁰ is chosen from OH, H and C₁-C₃ alkyl optionally substituted with    N(R⁹)₂;-   R¹¹ is chosen from H, CH₃ and CF₃; and-   R¹² is C₁-C₃ alkyl.

Provided is a pharmaceutical composition, comprising a compound of anyone of Formulae I-IX, together with at least one pharmaceuticallyacceptable vehicle chosen from carriers, adjuvants, and excipients.

Provided is a packaged pharmaceutical composition, comprising

a pharmaceutical composition described herein; and

instructions for using the composition to treat a patient suffering froma disease responsive to inhibition of Btk activity.

Provided is a method for treating a patient having a disease responsiveto inhibition of Btk activity, comprising administering to the patientan effective amount of a compound of any one of Formulae I-IX.

Provided is a method for treating a patient having a disease chosen fromcancer, bone disorders, autoimmune diseases, inflammatory diseases,acute inflammatory reactions, and allergic disorders comprisingadministering to the patient an effective amount of a compound of anyone of Formulae I-IX.

Provided is a method for increasing sensitivity of cancer cells tochemotherapy, comprising administering to a patient undergoingchemotherapy with a chemotherapeutic agent an amount of a compound ofany one of Formulae I-IX sufficient to increase the sensitivity ofcancer cells to the chemotherapeutic agent.

Provided is a method of reducing medication error and enhancingtherapeutic compliance of a patient being treated for a diseaseresponsive to inhibition of Btk activity, the method comprisingproviding a packaged pharmaceutical preparation described herein whereinthe instructions additionally include contraindication and adversereaction information pertaining to the packaged pharmaceuticalcomposition.

Provided is a method for inhibiting ATP hydrolysis, the methodcomprising contacting cells expressing Btk with a compound of any one ofFormulae I-IX in an amount sufficient to detectably decrease the levelof ATP hydrolysis in vitro.

Provided is a method for determining the presence of Btk in a sample,comprising contacting the sample with a compound of any one of FormulaeI-IX under conditions that permit detection of Btk activity, detecting alevel of Btk activity in the sample, and therefrom determining thepresence or absence of Btk in the sample.

Provided is a method for inhibiting B-cell activity comprisingcontacting cells expressing Btk with a compound of any one of FormulaeI-IX in an amount sufficient to detectably decrease B-cell activity invitro.

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise. The following abbreviations and terms have the indicatedmeanings throughout.

As used herein, when any variable occurs more than one time in achemical formula, its definition on each occurrence is independent ofits definition at every other occurrence. In accordance with the usualmeaning of “a” and “the” in patents, reference, for example, to “a”kinase or compound or “the” kinase or compound is inclusive of one ormore kinases or compounds. The broken bond

indicates the point of attachment.

As used herein, “alkyl” encompasses straight chain and branchedhydrocarbon chain having the indicated number of carbon atoms. Forexample C₁-C₆ alkyl encompasses both straight and branched chain alkylof from 1 to 6 carbon atoms. Examples of alkyl groups include methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl,2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl,and the like. When an alkyl residue having a specific number of carbonsis named, all geometric isomers having that number of carbons areintended to be encompassed; thus, for example, “butyl” is meant toinclude n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” includesn-propyl and isopropyl.

As used herein, “modulation” refers to a change in kinase activity as adirect or indirect response to the presence of compounds describedherein, relative to the activity of the kinase in the absence of thecompound. The change may be an increase in activity or a decrease inactivity, and may be due to the direct interaction of the compound withthe kinase, or due to the interaction of the compound with one or moreother factors that in turn affect kinase activity. For example, thepresence of the compound may, for example, increase or decrease kinaseactivity by directly binding to the kinase, by causing (directly orindirectly) another factor to increase or decrease the kinase activity,or by (directly or indirectly) increasing or decreasing the amount ofkinase present in the cell or organism.

Compounds of any one of Formulae I-IX include, but are not limited to,optical isomers of Formulae I-IX, racemates, and other mixtures thereof.In those situations, the single enantiomers or diastereomers, i.e.,optically active forms, can be obtained by asymmetric synthesis or byresolution of the racemates. Resolution of the racemates can beaccomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral high-pressure liquid chromatography (HPLC)column. In addition, compounds include Z- and E-forms (or cis- andtrans-forms) of compounds with carbon-carbon double bonds. Wherecompounds exist in various tautomeric forms, chemical entities of thepresent invention include all tautomeric forms of the compound.Compounds also include crystal forms including polymorphs andclathrates.

The present invention includes, but is not limited to, compounds ofFormulae I-IX and all pharmaceutically acceptable forms thereof.Pharmaceutically acceptable forms of the compounds recited hereininclude pharmaceutically acceptable salts, solvates, prodrugs, andmixtures thereof. In certain embodiments, the compounds describedherein, are in the form of pharmaceutically acceptable salts. Thecompounds of this invention remain part of this invention even when theyare in the form of chemical association with other chemical entities inthe manner of a chelate or a non-covalent complex. The terms “compound”and “chemical entity” are used interchangeably herein.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochlorate, phosphate,diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts;as well as salts with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate,salicylate, stearate, and alkanoate such as acetate, HOOC—(CH₂)_(n)—COOHwhere n is 0-4, and like salts. Similarly, pharmaceutically acceptablecations include, but are not limited to sodium, potassium, calcium,aluminum, lithium, and ammonium.

In addition, if the compound is obtained as an acid addition salt, thefree base can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts.

As noted above, prodrugs also fall within the scope of the presentinvention, for example ester or amide derivatives of the compounds ofany one Formulae I-IX. The term “prodrugs” includes any compounds thatbecome compounds of any one of Formulae I-IX when administered to apatient, e.g., upon metabolic processing of the prodrug. Examples ofprodrugs include, but are not limited to, acetate, formate, and benzoateand like derivatives of functional groups (such as alcohol or aminegroups) in the compounds of any one of Formulae I-IX.

The term “solvate” refers to the chemical entity formed by theinteraction of a solvent and a compound. Suitable solvates arepharmaceutically acceptable solvates, such as hydrates, includingmonohydrates and hemi-hydrates.

The term “chelate” refers to the chemical entity formed by thecoordination of a compound to a metal ion at two (or more) points. Sucha metal ion include Ca⁺⁺ and Mg⁺⁺.

The term “non-covalent complex” refers to the chemical entity formed bythe interaction of a compound and another molecule wherein a covalentbond is not formed between the compound and the molecule. For example,complexation can occur through van der Waals interactions, hydrogenbonding, and electrostatic interactions (also called ionic bonding).

The term “hydrogen bond” refers to a form of association between anelectronegative atom (also known as a hydrogen bond acceptor) and ahydrogen atom attached to a second, relatively electronegative atom(also known as a hydrogen bond donor). Suitable hydrogen bond donor andacceptors are well understood in medicinal chemistry (G. C. Pimentel andA. L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R.Taylor and a Kennard, “Hydrogen Bond Geometry in Organic Crystals”,Accounts of Chemical Research, 17, pp. 320-326 (1984)).

The term “active agent” is used to indicate a chemical entity which hasbiological activity. In certain embodiments, an “active agent” is acompound having pharmaceutical utility. For example an active agent maybe an anti-cancer therapeutic.

The term “therapeutically effective amount” of a compound of thisinvention means an amount effective, when administered to a human ornon-human patient, to provide a therapeutic benefit such as ameliorationof symptoms, slowing of disease progression, or prevention of diseasee.g., a therapeutically effective amount may be an amount sufficient todecrease the symptoms of a disease responsive to inhibition of Btkactivity. In some embodiments, a therapeutically effective amount is anamount sufficient to reduce cancer symptoms, the symptoms of bonedisorders, the symptoms of an allergic disorder, the symptoms of anautoimmune and/or inflammatory disease, or the symptoms of an acuteinflammatory reaction. In some embodiments a therapeutically effectiveamount is an amount sufficient to decrease the number of detectablecancerous cells in an organism, detectably slow, or stop the growth of acancerous tumor. In some embodiments, a therapeutically effective amountis an amount sufficient to shrink a cancerous tumor. In certaincircumstances a patient suffering from cancer may not present symptomsof being affected. In some embodiments, a therapeutically effectiveamount of a compound/chemical entity is an amount sufficient to preventa significant increase or significantly reduce the detectable level ofcancerous cells or cancer markers in the patient's blood, serum, ortissues. In methods described herein for treating allergic disordersand/or autoimmune and/or inflammatory diseases and/or acute inflammatoryreactions, a therapeutically effective amount may also be an amountsufficient, when administered to a patient, to detectably slowprogression of the disease, or prevent the patient to whom thecompound/chemical entity is given from presenting symptoms of theallergic disorders and/or autoimmune and/or inflammatory disease, and/oracute inflammatory response. In certain methods described herein fortreating allergic disorders and/or autoimmune and/or inflammatorydiseases and/or acute inflammatory reactions, a therapeuticallyeffective amount may also be an amount sufficient to produce adetectable decrease in the amount of a marker protein or cell type inthe patient's blood or serum. For example, in some embodiments atherapeutically effective amount is an amount of a compound/chemicalentity described herein sufficient to significantly decrease theactivity of B-cells. In another example, in some embodiments atherapeutically effective amount is an amount of a compound of any oneof Formulae I-IX sufficient to significantly decrease the number ofB-cells. In another example, in some embodiments a therapeuticallyeffective amount is an amount of a compound of any one of Formulae I-IXsufficient to decrease the level of anti-acetylcholine receptor antibodyin a patient's blood with the disease myasthenia gravis.

The term “inhibition” indicates a significant decrease in the baselineactivity of a biological activity or process. “Inhibition of Btkactivity” refers to a decrease in Btk activity as a direct or indirectresponse to the presence of a compound of any one of Formulae I-IX,relative to the activity of Btk in the absence of such compound. Thedecrease in activity may be due to the direct interaction of thecompound with Btk, or due to the interaction of such compound with oneor more other factors that in turn affect Btk activity. For example, thepresence of the compound may decrease Btk activity by directly bindingto the Btk, by causing (directly or indirectly) another factor todecrease Btk activity, or by (directly or indirectly) decreasing theamount of Btk present in the cell or organism.

Inhibition of Btk activity also refers to observable inhibition of Btkactivity in a standard biochemical assay for Btk activity, such as theATP hydrolysis assay described below. In some embodiments, a compound ofany one of Formulae I-IX has an IC₅₀ value less than or equal to 1micromolar. In some embodiments, a compound of any one of Formulae hasan IC₅₀ value less than or equal to less than 25 nanomolar. In someembodiments, a compound of any one of Formulae I-IX has an IC₅₀ valueless than or equal to 5 nanomolar.

“Inhibition of B-cell activity” refers to a decrease in B-cell activityas a direct or indirect response to the presence of a compound of anyone of Formulae I-IX, relative to the activity of B-cells in the absenceof such compound. The decrease in activity may be due to the directinteraction of the compound with Btk or with one or more other factorsthat in turn affect B-cell activity.

Inhibition of B-cell activity also refers to observable inhibition ofCD86 expression in a standard assay such as the assay described below.In some embodiments, a compound of any one of Formulae I-IX has an IC₅₀value less than or equal to 10 micromolar. In some embodiments, acompound of any one of Formulae I-IX has an IC₅₀ value less than orequal to less than 0.5 micromolar. In some embodiments, a compound ofany one of Formulae I-IX has an IC₅₀ value less than or equal to 100nanomolar.

“B cell activity” also includes activation, redistribution,reorganization, or capping of one or more various B cell membranereceptors, e.g., CD40, CD86, and Toll-like receptors TLRs (in particularTLR⁴), or membrane-bound immunoglobulins, e.g, IgM, IgG, and IgD. Most Bcells also have membrane receptors for Fc portion of IgG in the form ofeither antigen-antibody complexes or aggregated IgG. B cells also carrymembrane receptors for the activated components of complement, e.g.,C3b, C3d, C4, and Clq. These various membrane receptors andmembrane-bound immunoglobulins have membrane mobility and can undergoredistribution and capping that can initiate signal transduction.

B cell activity also includes the synthesis or production of antibodiesor immunoglobulins. Immunoglobulins are synthesized by the B cell seriesand have common structural features and structural units. Fiveimmunoglobulin classes, i.e., IgG, IgA, IgM, IgD, and IgE, arerecognized on the basis of structural differences of their heavy chainsincluding the amino acid sequence and length of the polypeptide chain.Antibodies to a given antigen may be detected in all or several classesof immunoglobulins or may be restricted to a single class or subclass ofimmunoglobulin Autoantibodies or autoimmune antibodies may likewisebelong to one or several classes of immunoglobulins. For example,rheumatoid factors (antibodies to IgG) are most often recognized as anIgM immunoglobulin, but can also IgG or IgA.

In addition, B cell activity also is intended to include a series ofevents leading to B cell clonal expansion (proliferation) from precursorB lymphocytes and differentiation into antibody-synthesizing plasmacells which takes place in conjunction with antigen-binding and withcytokine signals from other cells.

“Inhibition of B-cell proliferation” refers to inhibition ofproliferation of abnormal B-cells, such as cancerous B-cells, e.g.lymphoma B-cells and/or inhibition of normal, non-diseased B-cells. Theterm “inhibition of B-cell proliferation” indicates no increase or anysignificant decrease in the number of B-cells, either in vitro or invivo. Thus an inhibition of B-cell proliferation in vitro would be anysignificant decrease in the number of B-cells in an in vitro samplecontacted with a compound of any one of Formulae I-IX as compared to amatched sample not contacted with such compound.

Inhibition of B-cell proliferation also refers to observable inhibitionof B-cell proliferation in a standard thymidine incorporation assay forB-cell proliferation, such as the assay described herein. In someembodiments, a compound of any one of Formulae I-IX has an IC₅₀ valueless than or equal to 10 micromolar. In some embodiments, a compound ofany one of Formulae I-IX has an IC₅₀ value less than or equal to lessthan 500 nanomolar. In some embodiments, a compound of any one ofFormulae I-IX has an IC₅₀ value less than or equal to 50 nanomolar.

An “allergy” or “allergic disorder” refers to acquired hypersensitivityto a substance (allergen). Allergic conditions include eczema, allergicrhinitis or coryza, hay fever, bronchial asthma, urticaria (hives) andfood allergies, and other atopic conditions.

“Asthma” refers to a disorder of the respiratory system characterized byinflammation, narrowing of the airways and increased reactivity of theairways to inhaled agents. Asthma is frequently, although notexclusively associated with atopic or allergic symptoms.

By “significant” is meant any detectable change that is statisticallysignificant in a standard parametric test of statistical significancesuch as Student's T-test, where p<0.05.

A “disease responsive to inhibition of Btk activity” is a disease inwhich inhibiting Btk kinase provides a therapeutic benefit such as anamelioration of symptoms, decrease in disease progression, prevention ordelay of disease onset, or inhibition of aberrant activity of certaincell-types (monocytes, osteoclasts, B-cells, mast cells, myeloid cells,basophils, macrophages, neutrophils, and dendritic cells).

“Treatment or treating” means any treatment of a disease in a patient,including:

-   -   a) inhibiting the disease;    -   b) slowing or arresting the development of clinical symptoms;        and/or    -   c) relieving the disease, that is, causing the regression of        clinical symptoms.

“Prevent or preventing” a disease means causing the clinical symptoms ofthe disease not to develop.

“Patient” refers to an animal, such as a mammal, that has been or willbe the object of treatment, observation or experiment. The methods ofthe invention can be useful in both human therapy and veterinaryapplications. In some embodiments, the patient is a mammal; in someembodiments the patient is human; and in some embodiments the patient ischosen from cats and dogs.

Provided is a compound of Formula I:

and pharmaceutically acceptable salts, solvates, and mixtures thereof,wherein

-   X is chosen from N and CR²;-   Y is chosen from N and CR^(3′);-   Z is chosen from N and CR³; provided that only one of X, Y and Z is    N at a time;-   W is chosen from N and CH;-   V is chosen from CH and N; provided that one of W and V must be N    and W and V are not both N;-   R¹ is chosen from:

-   R² is chosen from H, CH₃, F, Cl, CN, OCH₃, OH and CF₃;-   R^(2′) is chosen from H and F;-   R³ is chosen from H, CH₃, CF₃, F, Cl, CN and OCH₃;-   R^(3′) is chosen from H, CH₃, F, Cl, CN and OCH₃;-   R⁴ is

-   m is chosen from 0 and 1;-   n is chosen from 0 and 1;-   R⁵ is chosen from H, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl, wherein said    alkyl is optionally substituted with one or more substituents chosen    from OH, F, and OCH₃;-   R⁶ is chosen from H and C₁-C₆ alkyl; or R⁵ and R⁶ are optionally    taken together with the nitrogen atom to which they are attached to    form a 4- to 6-membered cyclic ring having 0-1 additional N, S or O,    wherein the optional additional ring nitrogen is optionally    substituted with C₁-C₃ alkyl and said cyclic ring is optionally    substituted with OH;-   R⁷ is chosen from H, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl, wherein said    alkyl is optionally substituted with one or more substituents chosen    from OH and O(C₁-C₄ alkyl); or R⁶ and R⁷ are optionally taken    together with the —N(R⁵)C(R⁹)(CH₂)_(n)C(═O)N(R⁸)— group through the    respective nitrogen atoms to which they are directly attached to    form a 6-membered cyclic ring;-   R⁸ is chosen from H and C₁-C₆ alkyl, wherein said alkyl is    optionally substituted with one or more substituents chosen from OH,    F, and OCH₃; or R⁷ and R⁸ are optionally taken together with the    nitrogen atom to which they are attached to form a 4- to 6-membered    cyclic ring having 0-1 additional N, S or O, wherein the optional    additional ring nitrogen is optionally substituted with C₁-C₃ alkyl    and said cyclic ring is optionally substituted with OH;-   R⁹ is chosen from H and CH₃;-   R¹⁰ is chosen from OH, H and C₁-C₃ alkyl optionally substituted with    N(R⁹)₂;-   R¹¹ is chosen from H, CH₃ and CF₃; and-   R¹² is C₁-C₃ alkyl.

In certain embodiments, R¹¹ is CH₃. In certain embodiments, R¹¹ is H.

In certain embodiments, R¹² is C₁-C₂ alkyl.

In certain embodiments, W is N and V is CH (Formula I-a, wherein R¹,R^(2′), R⁴, R¹⁰, X, Y and Z are as defined in Formula I).

In certain embodiments, W is CH and V is N (Formula I-b, wherein R¹,R²², R⁴, R¹⁰, X, Y and Z are as defined in Formula I).

In certain embodiments, X is CR².

In certain embodiments, the compounds of the present invention are ofFormula II wherein R¹, R², R^(2′), R⁴, R¹⁰, Y and Z are as defined inFormula I.

In certain embodiments, X is N.

In certain embodiments, the compounds of the present invention are ofFormula III wherein R¹, R^(2′), R³, R^(3′), R⁴, and R¹⁰ are as definedin Formula I.

In certain embodiments, Y is CR^(3′).

In certain embodiments, the compounds of the present invention are ofFormula IV wherein R¹, R², R^(3′), R⁴, R¹⁰, X and Z are as defined inFormula I.

In certain embodiments, Y is N.

In certain embodiments, the compounds of the present invention are ofFormula V wherein R¹, R², R^(2′), R³, R⁴, and R¹⁰ are as defined inFormula I.

In certain embodiments, Z is CR³.

In certain embodiments, the compounds of the present invention are ofFormula VI wherein R¹, R^(2′), R³, R⁴, R¹⁰, X and Y are as defined inFormula I.

In certain embodiments, Z is N.

In certain embodiments, the compounds of the present invention are ofFormula VII wherein R¹, R², R^(2′), R^(3′), R⁴, R¹⁰, and Z are asdefined in Formula I.

In certain embodiments, the compounds of the present invention are ofFormula VIII wherein R¹, R², R^(2′), R³, R^(3′), R⁴, and R¹⁰ are asdefined in Formula I.

In certain embodiments, R^(2′) is H.

In certain embodiments, R^(2′) is F.

In certain embodiments, the compounds of the present invention are ofFormula IX, wherein:

-   R¹ is chosen from:

-   R² is chosen from H, CH₃, F, and Cl;-   R³ is chosen from H, CH₃, F, and Cl;-   R^(3′) is chosen from H, CH₃, F and Cl;-   R⁴ is

-   m is chosen from 0 and 1;-   n is chosen from 0 and 1;-   R⁵ is chosen from H and C₁-C₆ alkyl;-   R⁶ is chosen from H and C₁-C₆ alkyl; or R⁵ and R⁶ are optionally    taken together with the nitrogen atom to which they are attached to    form a 6-membered cyclic ring having 0-1 additional N, S or O,    wherein the optional additional ring nitrogen is optionally    substituted with C₁-C₃ alkyl;-   R⁷ is chosen from H and C₁-C₆ alkyl wherein said alkyl is optionally    substituted with one or more substituents chosen from OH and O(C₁-C₄    alkyl); or R⁶ and R⁷ are optionally taken together with the    —N(R⁵)C(R⁹)(CH₂)_(n)C(═O)N(R⁸)— group through the respective    nitrogen atoms to which they are directly attached to form a    6-membered cyclic ring;-   R⁸ is chosen from H and C₁-C₆ alkyl; or R⁷ and R⁸ are optionally    taken together with the nitrogen atom to which they are attached to    form a 4- to 6-membered cyclic ring having 0-1 additional N, S or O,    wherein the optional additional ring nitrogen is optionally    substituted with C₁-C₃ alkyl;-   R⁹ is chosen from H and CH₃; and-   R¹⁰ is chosen from H and C₁-C₃ alkyl.

In certain embodiments, in is 0. In certain embodiments, n is 0.

In certain embodiments, R¹ is chosen from:

In certain embodiments, R² is chosen from:

In certain embodiments, R² is chosen from CH₃, F, Cl, and H.

In certain embodiments, R² is chosen from CH₃, F, Cl and CN. In certainembodiments, R² is chosen from CH₃, F, and Cl. In certain embodiments,R² is CH₃.

In certain embodiments, R³ is chosen from H, CH₃, F and Cl. In certainembodiments, R³ is H. In certain embodiments, R³ is chosen from F andCl. In certain embodiments, R³ is chosen from CH₃ and OCH₃.

In certain embodiments, R^(3′) is chosen from H, CH₃, F and Cl. Incertain embodiments, R^(3′) is chosen from H, CH₃, F, Cl, and CN. Incertain embodiments, R^(3′) is H. In certain embodiments, R^(3′) ischosen from CH₃ and F. In certain embodiments, R^(3′) is chosen from Cland CN.

In certain embodiments, R⁵ is chosen from H and C₁-C₃ alkyl optionallysubstituted with OH. In certain embodiments, R⁵ is chosen from H andC_(1 C) ₆ alkyl. In certain embodiments, R⁵ is chosen from H and C₁-C₃alkyl. In certain embodiments, R⁵ is chosen from H, methyl, ethyl and—(CH₂)₂OH. In certain embodiments, R⁵ is chosen from H, methyl, andethyl.

In certain embodiments, R⁶ is chosen from H and C₁-C₃ alkyl. In certainembodiments, R⁶ is chosen from H, methyl, ethyl, n-propyl and i-propyl.In certain embodiments, R⁶ is chosen from H, methyl and ethyl.

In certain embodiments, R⁵ and R⁶ are taken together with the nitrogenatom to which they are attached to form a 4- or 6-membered cyclic ringhaving 0-1 additional N, S or O, wherein the optional additional ringnitrogen is optionally substituted with C₁-C₃ alkyl. In certainembodiments, R⁵ and R⁶ are taken together with the nitrogen atom towhich they are attached to form a 6-membered cyclic ring having 0-1additional N, S or O, wherein the optional additional ring nitrogen isoptionally substituted with C₁-C₃ alkyl. In certain embodiments, R⁵ andR⁶ are taken together with the nitrogen atom to which they are attachedto form azetidinyl, N-methylpiperazinyl, N-ethylpiperazinyl ormorpholinyl. In certain embodiments, R⁵ and R⁶ are taken together withthe nitrogen atom to which they are attached to form N-methylpiperazinylor N-ethylpiperazinyl.

In certain embodiments, R⁷ is chosen from H, methyl, ethyl, —(CH₂)₂OH,and —(CH₂)₂OCH₃. In certain embodiments, R⁷ is chosen from H, methyl,—(CH₂)₂OH, and —(CH₂)₂OCH₃. In certain embodiments, R⁶ and R⁷ are takentogether with —N(R⁵)C(R⁹)(CH₂)_(n)C(═O)N(R⁸)— group through therespective nitrogen atoms to which they are directly attached to form a6-membered cyclic ring (e.g.,

In certain embodiments, R⁸ is chosen from H and C₁-C₃ alkyl. In certainembodiments, R⁸ is chosen from H, methyl and ethyl. In certainembodiments, R⁷ and R⁸ are taken together with the nitrogen atom towhich they are attached to form a 4- to 6-membered cyclic ring having0-1 additional N, S or O, wherein the optional additional ring nitrogenis optionally substituted with C₁-C₃ alkyl. In certain embodiments, R⁷and R⁸ are taken together with the nitrogen atom to which they areattached to form a 4- or 6-membered cyclic ring having 0-1 additional Nor O, wherein the optional additional ring nitrogen is optionallysubstituted with methyl or ethyl and said cyclic ring is optionallysubstituted with OH. In certain embodiments, R⁷ and R⁸ are takentogether with the nitrogen atom to which they are attached to formN-methylpiperazinyl, N-ethylpiperazinyl, morpholinyl, or azetidinyloptionally substituted with OH. In certain embodiments, R⁷ and R⁸ aretaken together with the nitrogen atom to which they are attached to formmorpholinyl or azetidinyl.

In certain embodiments, R⁹ is H. In certain embodiments, R⁹ is methyl.

In certain embodiments, R¹⁰ is chosen from H and CH₃. In certainembodiments, R¹⁰ is H. In certain embodiments, R¹⁰ is —(CH₂)₃N(CH₃)₂. Incertain embodiments, R¹⁰ is OH.

In R⁵-R⁸ and R¹⁰, where optionally substituted alkyl or a cyclic ring issubstituted, in certain embodiments there are 1-3 substituents and thesecan replace any H atom. In R⁵-R⁸ and R¹⁰, in certain embodiments cyclicrings are saturated.

In certain embodiments, R contains a thiophene ring fused to a 5, 6, 7or 8 membered ring as shown herein. In certain embodiments, R¹ containsa phenylene or benzo ring as shown herein. In certain embodiments, R⁵,R⁶, R⁷ and/or R⁸ form a cyclic ring and in certain embodiments, R⁵, R⁶,R⁷ and/or R⁸ are non-cyclic, as shown herein.

In certain embodiments, the compound of Formula I is chosen from

-   N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(1-(Ethyl(isopropyl)amino)-2-(2-methoxyethyl)(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(1,2-Bis(4-ethylpiperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(1,2-Bis(4-ethyl    piperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(1-Ethyl-4-methyl-3-oxopiperazin-2-yl)    phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   4-tert-Butyl-N-(3-(6-(4-(1-ethyl-4-methyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydro    pyrazin-2-yl)-2-methylphenyl)benzamide;-   (S)-N-(3-(6-(4-(3-(Dimethylamino)-2-(isopropyl(methyl)amino)-3-oxopropyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(3-(Dimethylamino)-1-(isopropyl(methyl)amino)-3-oxopropyl)phenyl    amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methyl    phenyl)-4,5,6,7-tetrahydro benzo[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(1-Amino-2-morpholino-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4-tert-butylbenzamide;-   N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   4-tert-Butyl-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-ethyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;-   N-(3-(6-(4-(2-Amino-1-(isopropyl(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydro    pyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-Methyl-3-(4-methyl-6-(4-(1-methyl-3-oxopiperazin-2-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(2-(Dimethylamino)-1-(isopropyl(methyl)amino)-2-oxoethyl)phenyl    amino)-4-methyl-5-oxo-4,5-dihydro    pyrazin-2-yl)-2-methyphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   4-tert-Butyl-N-(3-(6-(4-(2-(dimethylamino)-1-(isopropyl(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;-   N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,5-difluorophenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   (S)-4-tert-Butyl-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;-   (R)-4-tert-Butyl-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;-   N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-5-oxo-4,5-dihydro    pyrazin-2-yl)-2-methylphenyl)-4-(ethyl(methyl)amino)benzamide;-   (R)-N-(3-(6-(4-(2-(Dimethylamino)-1-(isopropyl(methyl)amino)-2-oxoethyl)phenyl    amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4-(1-ethylcyclopropyl)benzamide;-   4-tert-Butyl-N-(3-(6-(4-(1-(4-ethylpiperazin-1-yl)-2-morpholino-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;-   N-(3-(6-(4-(1-(4-Ethylpiperazin-1-yl)-2-morpholino-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydro    pyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(1-(4-ethylpiperazin-1-yl)-2-morpholino-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methyl    phenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(1,2-Bis(4-ethyl    piperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4-tert-butylbenzamide;-   4-tert-Butyl-N-(3-(6-(4-(2-(dimethylamino)-1-(4-ethylpiperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;-   N-(3-(6-(4-(2-(Dimethylamino)-1-(4-ethylpiperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(2-(Dimethylamino)-1-(4-ethylpiperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydro    pyrazin-2-yl)-2-methylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide;-   4-tent-Butyl-N-(3-(6-(4-(1-(4-ethylpiperazin-1-yl)-2-(2-methoxyethyl)(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;-   N-(3-(6-(4-(1-(4-Ethylpiperazin-1-yl)-2-((2-methoxyethyl)(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methyl    phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(1-(4-Ethylpiperazin-1-yl)-2-(2-methoxyethyl)(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydro    pyrazin-2-yl)-2-methylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(1-Isopropyl-4-methyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-5-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-Chloro-3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4-(ethyl(methyl)amino)benzamide;-   N-(3-(6-(4-(1-(Ethyl(isopropyl)amino)-2-morpholino-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydro    pyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(1-(Ethyl(isopropyl)amino)-2-(4-ethylpiperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methyl    phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(4-(2-(Dimethylamino)-1-(ethyl(isopropyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-{3-[6-({4-[2-(Azetidin-1-yl)-1-(morpholin-4-yl)-2-oxo    ethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydro    pyrazin-2-yl]-2-methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{2-Methyl-3-[4-methyl-6-({4-[(methylcarbamoyl)(morpholin-4-yl)methyl]phenyl}amino)-5-oxo-4,5-dihydropyrazin-2-yl]phenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{3-[6-({4-[2-(Azetidin-1-yl)-1-[ethyl(propan-2-yl)amino]-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{3-[6-({4-[(Dimethyl    carbamoyl)[ethyl(propan-2-yl)amino]methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,7H,    8H-cyclohepta[b]thiophene-2-carboxamide;-   N-{3-[6-({4-[1-(azetidin-1-yl)-2-(4-ethylpiperazin-1-yl)-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydro    pyrazin-2-yl]-2-methyl phenyl}-4H,5H,6H,7H,    8H-cyclohepta[b]thiophene-2-carboxamide;-   N-3-(6-{[4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-5-oxo-4,5-dihydro    pyrazin-2-yl)-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{3-[6-({4-[Azetidin-1-yl(dimethylcarbarnoyl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,    7H,8H-cyclohepta[b]thiophene-2-carboxamide;-   N-[2-Methyl-3-(4-methyl-5-oxo-6-{[4-(1,2,4-trimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[5-Chloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{3-[6-({4-[Azetidin-1-yl(dimethylcarbamoyl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4-tert-butylbenzamide;-   N-{3-[6-({4-[Azetidin-1-yl(dimethylcarbamoyl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-(3-{6-[(4-Azetidin-1-yl[(2-hydroxyethyl)(methyl)carbamoyl]methyl    phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{2-Methyl-3-[4-methyl-6-({4-[4-methyl-3-oxo-1-(propan-2-yl)piperazin-2-yl]phenyl}amino)-5-oxo-4,5-dihydropyrazin-2-yl]phenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;-   N-{3-[6-({4-[(4-Ethyl piperazin-1-yl)[(2-hydroxy    ethyl)(methyl)carbamoyl]methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,    7H,8H-cyclohepta[b]thiophene-2-carboxamide;-   N-{3-[6-({4-[(Diethyl    carbamoyl)(4-ethylpiperazin-1-yl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydro    pyrazin-2-yl]-2-methyl    phenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;-   4-tert-Butyl-N-(3-{6-[(4-{[ethyl(methyl)carbamoyl](4-ethylpiperazin-1-yl)methyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)benzamide;-   4-tert-Butyl-N-{3-[6-({4-[(diethylcarbamoyl)(4-ethylpiperazin-1-yl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}benzamide;-   N-[3-(6-{[4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-N-methyl-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[(4-{1-[methyl(propan-2-yl)amino]-2-(morpholin-4-yl)-2-oxoethyl}phenyl)amino]-5-oxo-4,5-dihydropyrazin-2-yl}phenyl)benzamide;-   N-{3-[6-({4-[2-(Azetidin-1-yl)-1-[methyl(propan-2-yl)amino]-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4-tert-butylbenzamide;-   N-{3-[6-({4-[1-(Azetidin-1-yl)-2-(morpholin-4-yl)-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-(3-{6-[(4-{Azetidin-1-yl[(2-hydroxyethyl)(methyl)carbamoyl]methyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4H,5H,6H,7H,    8H-cyclohepta[b]thiophene-2-carboxamide;-   4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[(4-{1-[methyl(propan-2-yl)amino]-2-(4-methylpiperazin-1-yl)-2-oxoethyl}phenyl)amino]-5-oxo-4,5-dihydropyrazin-2-yl}phenyl)benzamide;-   N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4-(1-methylcyclopropyl)benzamide;-   N-(3-(6-(4-(1-Ethyl-4-methyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide;-   4-tert-Butyl-N-(3-(6-(4-(4-isopropyl-4-methyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;-   N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   (S)-N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   (R)-N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;    and-   (S)-(+)-N-(3-(6-(4-(2-(Dimethylamino)-1-(isopropyl(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-N-methyl-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-(3-{6-[(4-{1-[ethyl(methyl)amino]-2-(4-ethylpiperazin-1-yl)-2-oxoethyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;-   N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-6-[ethyl(methyl)amino]pyridine-3-carboxamide;-   N-[3-(6-[{4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluoro-5-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-3-[6-({4-[2-(azetidin-1-yl)-1-[methyl(propan-2-yl)amino]-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl)-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;-   N-[3-(6-[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-{[4-(4-ethyl-1-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-{[4-(4-ethyl-1-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;-   N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,5-dimethylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[5-chloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{3-[6-({4-[(dimethylcarbamoyl)(morpholin-4-yl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{3-[6-({4-[(diethylcarbamoyl)(morpholin-4-yl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-(3-{6-[(4-[ethyl(methyl)carbamoyl](morpholin-4-yl)methyl    phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-(3-[6-[(4-{[(2-hydroxyethyl)(methyl)carbamoyl](morpholin-4-yl)    methyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl)-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{3-[6-({4-[2-(3-hydroxyazetidin-1-yl)-1-(morpholin-4-yl)-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{3-[6-({4-[(dimethylcarbamoyl)(morpholin-4-yl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;-   N-{3-[6-({4-[(diethylcarbamoyl)(morpholin-4-yl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,    5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;-   N-{3-[6-({4-[2-(azetidin-1-yl)-1-(morpholin-4-yl)-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;-   N-{2-methyl-3-[4-methyl-6-({4-[(methylcarbamoyl)(morpholin-4-yl)methyl]phenyl}amino)-5-oxo-4,5-dihydropyrazin-2-yl]phenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;-   N-(3-{6-[(4-{[ethyl(methyl)carbamoyl](morpholin-4-yl)methyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;-   N-(3-{6-[(4-{[(2-hydroxyethyl)(methyl)carbamoyl](morpholin-4-yl)methyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;-   N-{3-[6-({4-[2-(3-hydroxyazetidin-1-yl)-1-(morpholin-4-yl)-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;-   4-tent-butyl-N-[3-(6-[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-2-methoxybenzamide;-   N-[2-chloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-5-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-dimethylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-5-methoxy-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-difluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[5-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[2,6-dichloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[6-chloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[2-chloro-5-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[2-chloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[2-cyano-5-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[4-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoropyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   4-tert-butyl-N-{3-[6-({4-[(S)-(dimethylcarbamoyl)[methyl(propan-2-yl)amino]methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}benzamide;-   4-tert-butyl-N-{3-[6-({4-[(R)-(dimethylcarbamoyl)[methyl(propan-2-yl)amino]methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}benzamide;-   4-tert-butyl-N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-N-[3-(dimethylamino)propyl]benzamide;-   N-[6-chloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[5-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-3-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[6-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[2-chloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[6-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[6-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-5-fluoropyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-7-hydroxy-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   4-tert-butyl-N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-2-methylbenzamide;-   N-[3-(6-{[4-(1-ethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-[4-(1-ethyl-3-oxopiperazin-2-yl)phenyl]amino-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-difluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-{[4-(1-ethyl-4-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-difluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[5-(6-{[4-(4-ethyl-1-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   4-tert-butyl-N-[6-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2-yl]benzamide;-   N-[5-(6-[4-(1-ethyl-3-oxopiperazin-2-yl)phenyl]amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[5-(6-{[4-(1,4-diethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-{[4-(4-ethyl-1-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-difluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[5-(6-[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-7,7-difluoro-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[5-(6-{[4-(1-ethyl-4-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[6-(6-{[4-(4-ethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[6-(6-{[4-(4-ethyl-1-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[6-(6-{[4-(1-ethyl-4-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[6-(6-{[4-(1,4-diethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-{[4-(1,4-diethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-{[4-(4-ethyl-1-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-5-[6-({4-[(2R)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-{[4-(1,4-diethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-difluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{5-[6-({4-[(2S)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-fluorophenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{6-[6-({4-[(2S)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-fluoropyridin-2-yl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{6-[6-({4-[(2R)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-fluoropyridin-2-yl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[2-fluoro-5-(4-methyl-6-{[4-(4-methyl-3-oxopiperazin-2-yl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5    dihydropyrazin-2-yl)-2-fluoro-6-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-[4-(1-ethyl-4-methyl-3-oxopiperazin-2-yl)phenyl]amino-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[5-(6-{[4-(2,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{5-[6-({4-[2-(azetidin-1-yl)-1-(dimethylamino)-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-fluorophenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{2-fluoro-5-[6-({4-[1-(2-hydroxyethyl)-4-methyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]phenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[5-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,4-difluoro-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-4-hydroxy-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(5-{[5-(1,4-dimethyl-3-oxopiperazin-2-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;    and    pharmaceutically acceptable salts, solvates, and mixtures thereof.

The present compounds described herein are potent inhibitors of Btk.While not being bound by any theory, certain compounds have improvedproperties in the form of greater efficacy (as measured by, for example,the inhibition of Btk in whole blood and the inhibition of B-cellactivation in mice).

Methods for obtaining the novel compounds described herein will beapparent to those of ordinary skill in the art, suitable proceduresbeing described, for example, in the reaction schemes and examplesbelow, and in the references cited herein. See, also, U.S. applicationSer. No. 11/371,180 (US2006/0229337), filed Mar. 9, 2006, which isincorporated herein by reference in its entirety.

Referring to Reaction Scheme 1, Step 1, to a suspension of a compound ofFormula 201, bis(pinacolato)diboron, and a base such as potassiumacetate is added about 0.03 equivalent of [1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium (11) complex withdichloromethane (1:1). The reaction is heated at about 85° C. for about20 h. The product, a compound of Formula 203, is isolated and optionallypurified.

Referring to Reaction Scheme 1, Step 2, 10% palladium on charcoal isadded to a mixture of a compound of Formula 203 in a polar, proticsolvent such as methanol. To the mixture is added hydrogen gas. Thereaction is stirred under balloon pressure of hydrogen at roomtemperature for about 13 h. The product, a compound of Formula 205, isisolated and optionally purified.

Referring to Reaction Scheme 1, Step 3, a solution of about anequivalent of a compound of formula 206 in an inert solvent such asdichloromethane is added portionwise to a solution of a compound ofFormula 205 and a base such as triethylamine in an inert solvent such asdichloromethane. The mixture is stirred at room temperature for about 16h. The product, a compound of Formula 207, is isolated and optionallypurified.

Referring to Reaction Scheme 2, Step 1, a mixture of a compound ofFormula 301; an excess (such as about 1.2 equivalents) of bis(neopentylglycolato)diboron; and about 0.3 equivalent of[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium, 1:1 complexwith dichloromethane; and a base such as potassium acetate in an inertsolvent such as dioxane is heated at reflux for about 3 h. The product,a compound of Formula 305, is isolated and optionally purified.

Referring to Reaction Scheme 2, Step 2, a mixture of a compound ofFormula 303 and 10% palladium-on-carbon in an inert solvent such asethyl acetate methanol is, treated with 40 psi of hydrogen for about 2 hat room temperature. The product, a compound of Formula 305, is isolatedand optionally purified.

Referring to Reaction Scheme 2, Step 3, a solution of a compound ofFormula 305 and a base, such as triethylamine in an inert solvent suchas THF is treated dropwise with about an equivalent of an acid chlorideof the Formula 306 and the mixture is stirred at room temperature forabout 15 min. The product, a compound of Formula 307, is isolated andoptionally purified.

Referring to Reaction Scheme 3, Step 1, a mixture of a compound ofFormula 501, about an equivalent of a compound of NiI₂—R¹³, and an inertbase such as 1-methyl-2-pyrollidinone is heated at about 130° C. forabout 1 hr. The product, a compound of Formula 503, is isolated andoptionally purified, wherein R¹³ is

Referring to Reaction Scheme 3, Step 2, a mixture of a compound ofFormula 503, an excess (such as about 1.2 equivalents) of a compound ofFormula 107, about 0.05 equivalent oftetrakis(triphenylphosphine)palladium and a base such as 1N sodiumcarbonate in an inert solvent such as 1,2-dimethoxyethane is heated atabout 100° C. in a sealed pressure vessel for about 16 hr. The product,a compound of Formula 505, is isolated and optionally purified.

In some embodiments, compounds of any one of Formulae I-IX areadministered as a pharmaceutical composition or formulation.Accordingly, the invention provides pharmaceutical formulationscomprising a compound of any one of Formulae I-IX and pharmaceuticallyacceptable salts, solvates, and mixtures thereof, together with at leastone pharmaceutically acceptable vehicle chosen from carriers, adjuvants,and excipients.

Pharmaceutically acceptable vehicles must be of sufficiently high purityand sufficiently low toxicity to render them suitable for administrationto the animal being treated. The vehicle can be inert or it can possesspharmaceutical benefits. The amount of vehicle employed in conjunctionwith the compound is sufficient to provide a practical quantity ofmaterial for administration per unit dose of the compound.

Exemplary pharmaceutically acceptable carriers or components thereof aresugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; synthetic oils; vegetable oils,such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil;polyols such as propylene glycol, glycerine, sorbitol, mannitol, andpolyethylene glycol; alginic acid; phosphate buffer solutions;emulsifiers, such as the TWEENS; wetting agents, such as sodium laurylsulfate; coloring agents; flavoring agents; tableting agents;stabilizers; antioxidants; preservatives; pyrogen-free water; isotonicsaline; and phosphate buffer solutions.

Optional active agents may be included in a pharmaceutical composition,which do not substantially interfere with the activity of the compoundof the present invention.

Effective concentrations of a compound of any one of Formulae I-IX andpharmaceutically acceptable salts, solvates, and mixtures thereof, aremixed with a suitable pharmaceutical acceptable vehicle. In instances inwhich the compound exhibits insufficient solubility, methods forsolubilizing compounds may be used. Such methods are known to those ofskill in this art, and include, but are not limited to, usingcosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such asTWEEN, or dissolution in aqueous sodium bicarbonate.

Upon mixing or addition of the compound of any one of Formulae I-IX, theresulting mixture may be a solution, suspension, emulsion or the like.The form of the resulting mixture depends upon a number of factors,including the intended mode of administration and the solubility of thecompound in the chosen vehicle. The effective concentration sufficientfor ameliorating the symptoms of the disease treated may be empiricallydetermined.

Compounds of any one of Formulae I-IX may be administered orally,topically, parenterally, intravenously, by intramuscular injection, byinhalation or spray, sublingually, transdermally, via buccaladministration, rectally, as an ophthalmic solution, or by other means,in dosage unit formulations.

Dosage formulations suitable for oral use, include, for example,tablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agents, suchas sweetening agents, flavoring agents, coloring agents and preservingagents, in order to provide pharmaceutically elegant and palatablepreparations. In some embodiments, oral formulations contain from 0.1 to99% of a compound of any one of Formulae I-IX. In some embodiments, oralformulations contain at least 5% (weight %) of a compound of Formula I.Some embodiments contain from 25% to 50% or from 5% to 75% of a compoundof any one of Formulae I-IX.

Orally administered compositions also include liquid solutions,emulsions, suspensions, powders, granules, elixirs, tinctures, syrups,and the like. The pharmaceutically acceptable carriers suitable forpreparation of such compositions are well known in the art. Oralformulations may contain preservatives, flavoring agents, sweeteningagents, such as sucrose or saccharin, taste-masking agents, and coloringagents.

Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. Syrups and elixirs may beformulated with, sweetening agents, for example glycerol propyleneglycol, sorbitol, or sucrose. Such formulations may also contain ademulcent.

Compounds of any one of Formulae I-IX can be incorporated into oralliquid preparations such as aqueous or oily suspensions, solutions,emulsions, syrups, or elixirs, for example. Moreover, formulationscontaining these chemical entities can be presented as a dry product forconstitution with water or other suitable vehicle before use. Suchliquid preparations can contain conventional additives, such assuspending agents (e.g., sorbitol syrup, methyl cellulose,glucose/sugar, syrup, gelatin, hydroxyethyl cellulose, carboxymethylcellulose, aluminum stearate gel, and hydrogenated edible fats),emulsifying agents (e.g., lecithin, sorbitan monsoleate, or acacia),non-aqueous vehicles, which can include edible oils (e.g., almond oil,fractionated coconut oil, silyl esters, propylene glycol and ethylalcohol), and preservatives (e.g., methyl or propyl p-hydroxybenzoateand sorbic acid).

For a suspension, typical suspending agents include methylcellulose,sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodiumalginate; typical wetting agents include lecithin and polysorbate 80;and typical preservatives include methyl paraben and sodium benzoate.

Aqueous suspensions contain the active material(s) in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients include suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents; naturally-occurring phosphatides, forexample, lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol substitute, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan substitute.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example peanut oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or peanut oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.

Tablets typically comprise conventional pharmaceutically acceptableadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, can beuseful adjuvants for chewable tablets. Capsules (including time releaseand sustained release formulations) typically comprise one or more soliddiluents disclosed above. The selection of carrier components oftendepends on secondary considerations like taste, cost, and shelfstability.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the compound is releasedin the gastrointestinal tract in the vicinity of the desired topicalapplication, or at various times to extend the desired action. Suchdosage forms typically include, but are not limited to, one or more ofcellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes andshellac.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent; forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Pharmaceutical compositions may be in the form of a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents that have been mentioned above. The sterileinjectable preparation may also be sterile injectable solution orsuspension in a non-toxic parentally acceptable vehicle, for example asa solution in 1,3-butanediol. Among the acceptable vehicles that may beemployed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid can be useful in the preparation ofinjectables.

Compounds of any one of Formulae I-IX may be administered parenterallyin a sterile medium. Parenteral administration includes subcutaneousinjections, intravenous, intramuscular, intrathecal injection orinfusion techniques. Compounds of any one of Formulae I-IX, depending onthe vehicle and concentration used, can either be suspended or dissolvedin the vehicle. Advantageously, adjuvants such as local anesthetics,preservatives and buffering agents can be dissolved in the vehicle. Inmany compositions for parenteral administration the carrier comprises atleast 90% by weight of the total composition. In some embodiments, thecarrier for parenteral administration is chosen from propylene glycol,ethyl oleate, pyrrolidone, ethanol, and sesame oil.

Compounds of any one of Formulae I-IX may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at rectal temperature and will therefore melt in the rectum torelease the drug. Such materials include cocoa butter and polyethyleneglycols.

Compounds of any one of Formulae I-IX may be formulated for local ortopical application, such as for topical application to the skin andmucous membranes, such as in the eye, in the faun of gels, creams, andlotions and for application to the eye. Topical compositions may be, inany form including, for example, solutions, creams, ointments, gels,lotions, milks, cleansers, moisturizers, sprays, skin patches, and thelike

Such solutions may be formulated as 0.01%-10% isotonic solutions, pH5-7, with appropriate salts. Compounds of any one of Formulae I-IX mayalso be formulated for transdermal administration as a transdermalpatch.

Topical compositions comprising a compound of any one of Formulae I-IXcan be admixed with a variety of carrier materials well known in theart, such as, for example, water, alcohols, aloe vera gel, allantoin,glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2myristyl propionate, and the like.

Other materials suitable for use in topical carriers include, forexample, emollients, solvents, humectants, thickeners and powders.Examples of each of these types of materials, which can be used singlyor as mixtures of one or more materials, are as follows:

Representative emollients include stearyl alcohol, glycerylmonoricinoleate, glyceryl monostearate, propane-1,2-dial,butane-1,3-diol, mink oil, cetyl alcohol, iso-propyl isostearate,stearic acid, iso-butyl palmitate, isocetyl stearate, oleyl alcohol,isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetylalcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate,iso-propyl myristate, iso-propyl palmitate, iso-propyl stearate, butylstearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil,coconut oil, araehis oil, castor oil, acetylated lanolin alcohols,petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid,isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, andmyristyl myristate; propellants, such as propane, butane, iso-butane,dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such asethyl alcohol, methylene chloride, iso-propanol, castor oil, ethyleneglycol monoethyl ether, diethylene glycol monobutyl ether, diethyleneglycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide,tetrahydrofuran; humectants, such as glycerin, sorbitol, sodium2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, andgelatin; and powders, such as chalk, talc, fullers earth, kaolin,starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetraalkyl ammonium smectites, trialkyl aryl ammonium smectites, chemicallymodified magnesium aluminium silicate, organically modifiedmontmorillonite clay, hydrated aluminium silicate, fumed silica,carboxyvinyl polymer, sodium carboxymethyl cellulose, and ethyleneglycol monostearate.

Compounds of any one of Formulae I-IX may also be topically administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine and phosphatidylcholines.

Other compositions useful for attaining systemic delivery of thecompound include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol, and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropylmethylcellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

Compositions for inhalation typically can be provided in the form of asolution, suspension or emulsion that can be administered as a drypowder or in the form of an aerosol using a conventional propellant(e.g., dichlorodifluoromethane or trichlorofluoromethane).

The compositions of the present invention may also optionally comprisean activity enhancer. The activity enhancer can be chosen from a widevariety of molecules that function in different ways to enhance or beindependent of therapeutic effects of the present compounds. Particularclasses of activity enhancers include skin penetration enhancers andabsorption enhancers.

Pharmaceutical compositions of the invention may also contain additionalactive agents that can be chosen from a wide variety of molecules, whichcan function in different ways to enhance the therapeutic effects of acompound of any one of Formulae I-IX. These optional other activeagents, when present, are typically employed in the compositions of theinvention at a level ranging from 0.01% to 15%. Some embodiments containfrom 0.1% to 10% by weight of the composition. Other embodiments containfrom 0.5% to 5% by weight of the composition.

The invention includes packaged pharmaceutical formulations. Suchpackaged formulations include a pharmaceutical composition comprising acompound of any one of Formulae I-IX and pharmaceutically acceptablesalts, solvates, and mixtures thereof, and instructions for using thecomposition to treat a mammal (typically a human patient). In someembodiments, the instructions are for using the pharmaceuticalcomposition to treat a patient suffering from a disease responsive toinhibition of Btk activity and/or inhibition of B-cell and/ormyeloid-cell activity. The invention can include providing prescribinginformation; for example, to a patient or health care provider, or as alabel in a packaged pharmaceutical formulation. Prescribing informationmay include for example efficacy, dosage and administration,contraindication and adverse reaction information pertaining to thepharmaceutical formulation.

In all of the foregoing the compounds of any one of Formulae I-IX can beadministered alone, as mixtures, or in combination with other activeagents.

Accordingly, the invention includes a method of treating a patient, forexample, a mammal, such as a human, having a disease responsive toinhibition of Btk activity, comprising administrating to the patienthaving such a disease, an effective amount of a compound of any one ofFormulae I-IX and pharmaceutically acceptable salts, solvates, andmixtures thereof.

To the extent that Btk is implicated in disease, alleviation of thedisease, disease symptoms, preventative, and prophylactic treatment iswithin the scope of this invention. In some embodiments, compounds ofany one of Formulae I-IX may also inhibit other kinases, such thatalleviation of disease, disease symptoms, preventative, and prophylactictreatment of conditions associated with these kinases is also within thescope of this invention.

Methods of treatment also include inhibiting Btk activity and/orinhibiting B-cell and/or myeloid-cell activity, by inhibiting ATPbinding or hydrolysis by Btk or by some other mechanism, in vivo, in apatient suffering from a disease responsive to inhibition of Btkactivity, by administering an effective concentration of a compound ofany one of Formulae I-IX and pharmaceutically acceptable salts,solvates, and mixtures thereof. An example of an effective concentrationwould be that concentration sufficient to inhibit Btk activity in vitro.An effective concentration may be ascertained experimentally, forexample by assaying blood concentration of the compound, ortheoretically, by calculating bioavailability.

In some embodiments, the condition responsive to inhibition of Btkactivity and/or B-cell and/or myeloid-cell activity is cancer, a bonedisorder, an allergic disorder and/or an autoimmune and/or inflammatorydisease, and/or an acute inflammatory reaction.

The invention includes a method of treating a patient having cancer, abone disorder, an allergic disorder and/or an autoimmune and/orinflammatory disease, and/or an acute inflammatory reaction, byadministering an effective amount of a compound of any one of FormulaeI-1× and pharmaceutically acceptable salts, solvates, and mixturesthereof.

In some embodiments, the conditions and diseases that can be affectedusing compounds of any one of Formulae I-IX, include, but are notlimited to: allergic disorders, including but not limited to eczema,allergic rhinitis or coryza, hay fever, bronchial asthma, urticaria(hives) and food allergies, and other atopic conditions;

autoimmune and/or inflammatory diseases, including but not limited topsoriasis, Crohn's disease, irritable bowel syndrome, Sjogren's disease,tissue graft rejection, and hyperacute rejection of transplanted organs,asthma, systemic lupus erythematosus (and associatedglomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma,vasculitis (ANCA-associated and other vasculitides), autoimmunehemolytic and thrombocytopenic states, Goodpasture's syndrome (andassociated glomerulonephritis and pulmonary hemorrhage),atherosclerosis, rheumatoid arthritis, osteoarthritis, chronicIdiopathic thrombocytopenic purpura (ITP), Addison's disease,Parkinson's disease, Alzheimer's disease, Diabetes mellitus (type 1),septic shock, myasthenia gravis, Ulcerative Colitis, Aplastic anemia,Coeliac disease, Wegener's granulomatosis and other diseases in whichthe cells and antibodies arise from and are directed against theindividual's own tissues; acute inflammatory reactions, including butnot limited to skin sunburn, inflammatory pelvic disease, inflammatorybowel disease, urethritis, uvitis, sinusitis, pneumonitis, encephalitis,meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis,gastritis, enteritis, dermatitis, gingivitis, appendicitis,pancreatitis, and cholocystitis; cancer, including but not limited tohematological malignancies, such as B-cell lymphoma, and acutelymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenousleukemia, chronic and acute lymphocytic leukemia, hairy cell leukemia,Hodgkin's disease, Non-Hodgkin lymphoma, multiple myeloma, and otherdiseases that are characterized by cancer of the blood or lymphaticsystem; and bone disorders, including but not limited to osteoporosis.

Btk is a known inhibitor of apoptosis in lymphoma B-cells. Defectiveapoptosis contributes to the pathogenesis and drug resistance of humanleukemias and lymphomas. Thus, further provided is a method of promotingor inducing apoptosis in cells expressing Btk comprising contacting thecell with a compound of any one of Formulae I-IX, pharmaceuticallyacceptable salts, solvates, and mixtures thereof.

The invention provides methods of treatment in which a compound of anyone of Formulae I-IX, and pharmaceutically acceptable salts, solvates,and mixtures thereof, or a composition (e.g., a pharmaceuticalcomposition thereof), is the only active agent given to a patient andalso includes methods of treatment in which a compound of any one ofFormulae I-IX, and pharmaceutically acceptable salts, solvates, andmixtures thereof, or a composition (e.g., a pharmaceutical compositionthereof), is given to a patient in combination with one or moreadditional active agents. The additional active agent(s) can be given toa patient sequentially or consecutively with a compound or compositionof the present invention.

The invention provides methods of treatment of rheumatoid arthritis,systemic lupus erythematosus, multiple sclerosis and/or asthma in whicha compound of any one of Formulae I-IX, and pharmaceutically acceptablesalts, solvates, and mixtures thereof, is the only active agent given toa patient and also includes methods of treatment of rheumatoidarthritis, systemic lupus erythematosus, multiple sclerosis and/orasthma in which a compound of any one of Formulae I-IX, andpharmaceutically acceptable salts, solvates, and mixtures thereof, isgiven to a patient in combination with one or more additional activeagents.

Thus in one embodiment the invention provides a method of treatingcancer, a bone disorder, an allergic disorder and/or an autoimmuneand/or inflammatory disease, and/or an acute inflammatory reaction,which comprises administering to a patient in need thereof an effectiveamount of a compound of any one of Formulae I-IX and pharmaceuticallyacceptable salts, solvates, and mixtures thereof, together with a secondactive agent, which can be useful for treating a cancer, a bonedisorder, an allergic disorder and/or an autoimmune and/or inflammatorydisease, and/or an acute inflammatory reaction. For example the secondagent may be an anti-inflammatory agent. Treatment with the secondactive agent may be prior to, concomitant with, or following treatmentwith a compound of any one of Formulae I-IX and pharmaceuticallyacceptable salts, solvates, and mixtures thereof. In certainembodiments, a compound of any one of Formulae I-IX and pharmaceuticallyacceptable salts, solvates, and mixtures thereof, is combined withanother active agent in a single dosage form. Suitable antitumortherapeutics that may be used in combination with a compound of any oneof Formulae I-IX include, but are not limited to, chemotherapeuticagents; for example mitomycin C, carboplatin, taxol, cisplatin,paclitaxel, etoposide, doxorubicin, or a combination comprising at leastone of the foregoing chemotherapeutic agents. Radiotherapeutic antitumoragents may also be used, alone or in combination with chemotherapeuticagents.

Compounds of any one of Formulae I-IX can be useful as chemosensitizingagents, and, thus, can be useful in combination with otherchemotherapeutic drugs, in particular, drugs that induce apoptosis.

A method for increasing sensitivity of cancer cells to chemotherapy,comprising administering to a patient undergoing chemotherapy achemotherapeutic agent together with a compound of any one of FormulaeI-IX and pharmaceutically acceptable salts, solvates, and mixturesthereof, in an amount sufficient to increase the sensitivity of cancercells to the chemotherapeutic agent is also provided herein.

Examples of other chemotherapeutic drugs that can be used in combinationwith the present compounds include topoisomerase I inhibitors(camptothesin or topotecan), topoisomerase II inhibitors (e.g.daunomycin and etoposide), alkylating agents (e.g. cyclophosphamide,melphalan and BCNU), tubulin directed agents (e.g. taxol andvinblastine), biological agents (e.g. antibodies such as anti CD20antibody, IDEC 8, immunotoxins, and cytokines), tyrosine kinaseinhibitors (e.g., Gleevac) and the like. Such examples of otherchemotherapeutic drugs that can be used in combination with the presentcompounds also include R—CHOP (cyclophosphamide (also calledCytoxan/Neosar), doxorubicin (or Adriamycin), vincristine (Oncovin) andprednisolone), ICE (ifosfamide, carboplatin, and etoposide), DHAP(dexamethasone, cisplatin, and cytarabine), ESHAP (etoposide,methylpredinsolone, cytarabine, and cisplatin), gemcitabine, Rituxan®,Treanda®, chlorambucil, fludarabine, alemtuzumab, and the like.

Included herein are methods of treatment, for example for treatingautoimmune and/or inflammatory diseases, in which a compound of any oneof Formulae I-IX and pharmaceutically acceptable salts, solvates, andmixtures thereof, is administered in combination with ananti-inflammatory agent. Anti-inflammatory agents include but are notlimited to NSAIDs, non-specific and COX-2 specific cyclooxygenase enzymeinhibitors, gold compounds, corticosteroids, methotrexate, tumornecrosis factor receptor (TNF) receptors antagonists, immunosuppressantsand methotrexate.

Examples of NSAIDs include, but are not limited to ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors (i.e., a compound that inhibits COX-2 with an IC₅₀ that is atleast 50-fold lower than the IC₅₀ for COX-1) such as celecoxib,valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib.

In a further embodiment, the anti-inflammatory agent is a salicylate.Salicylates include but are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be chosen from cortisone, dexamethasone,methylprednisolone, prednisolone, prednisolone sodium phosphate, andprednisone.

In additional embodiments the anti-inflammatory therapeutic agent is agold compound such as gold sodium thiomalate or auranofin.

The invention also includes embodiments in which the anti-inflammatoryagent is a metabolic inhibitor such as a dihydrofolate reductaseinhibitor, such as methotrexate or a dihydroorotate dehydrogenaseinhibitor, such as leflunomide. The second anti-inflammatory agent thatmay be used in combination with any one or more compounds of the presentinvention includes biologics and oral agents for treating rheumatoidarthritis.

Other embodiments of the invention pertain to combinations in which atleast one anti-inflammatory compound is an anti-05 monoclonal antibody(such as eculizumab or pexelizumab), a TNF antagonist, such asentanercept, infliximab, and adalimumab (Humira®) which are anti-TNFalpha monoclonal antibodies.

Still other embodiments of the invention pertain to combinations inwhich at least one active agent is an immunosuppressant compound such asmethotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, ormycophenolate mofetil.

Still other embodiments of the invention pertain to combinations withRituxan® (Rituximab) or other agents that work by selectively depletingCD20+ B-cells.

Dosage levels of the order, for example, of from 0.1 mg to 140 mg perkilogram of body weight per day can be useful in the treatment of theabove-indicated conditions (0.5 mg to 7 g per patient per day). Theamount of active ingredient that may be combined with the vehicle toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. Dosage unit forms willgenerally contain from 1 mg to 500 mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. In some embodiments, for example, for thetreatment of an allergic disorder and/or autoimmune and/or inflammatorydisease, a dosage regimen of 4 times daily or less is used. In someembodiments, a dosage regimen of 1 or 2 times daily is used. It will beunderstood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, and rate ofexcretion, drug combination and the severity of the particular diseasein the patient undergoing therapy.

A labeled form of a compound of the invention can be used as adiagnostic for identifying and/or obtaining compounds that have thefunction of modulating an activity of a kinase as described herein. Thecompounds of the invention may additionally be used for validating,optimizing, and standardizing bioassays.

By “labeled” herein is meant that the compound is either directly orindirectly labeled with a label which provides a detectable signal,e.g., radioisotope, fluorescent tag, enzyme, antibodies, particles suchas magnetic particles, chemiluminescent tag, or specific bindingmolecules, etc. Specific binding molecules include pairs, such as biotinand streptavidin, digoxin and antidigoxin etc. For the specific bindingmembers, the complementary member would normally be labeled with amolecule which provides for detection, in accordance with knownprocedures, as outlined above. The label can directly or indirectlyprovide a detectable signal.

The invention is further illustrated by the following non-limitingexamples.

EXAMPLE 1

Methyl 2-(4-Nitrophenyl)acetate (1)

A 1-L single-neck round-bottomed flask equipped with a magnetic stirrerand reflux condenser was charged with 4-nitrophenylacetic acid (14.1 g,77.5 mmol), anhydrous methanol (130 mL) and concentrated sulfuric acid(12.0 mL, 216 mmol), and the reaction mixture was heated at reflux for16 h. After this time, the reaction was concentrated to dryness underreduced pressure. The resulting residue was partitioned between water(500 mL) and diethyl ether (200 mL) and the layers separated. Theaqueous phase was extracted with diethyl ether (100 mL). The combinedorganic phases were washed with saturated aqueous sodium carbonate anddried over magnesium sulfate, and the drying agent was removed byfiltration. The filtrate was concentrated under reduced pressure anddried to a constant weight under vacuum to afford a 96% yield of 1 (14.6g) as a white solid: mp 45-46° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.19 (d,2H, J=8.5 Hz), 7.46 (d, 2H, J=8.5 Hz), 3.75 (s, 2H), 3.73 (s, 3H).Reference: Tetrahedron 2002, 58, 10113.

Methyl 2-Bromo-2-(4-nitrophenyl)acetate (2)

A 1-L single-neck round-bottomed flask equipped with a magnetic stirrerand reflux condenser was charged with 1 (10.6 g, 54.1 mmol), carbontetrachloride (120 mL), N-bromosuccinimide (10.7 g, 59.9 mmol) andazobisisobutylonitrile (275 mg, 1.67 mmol), and the reaction mixture washeated at reflux for 18 h. After this time the reaction was cooled toroom temperature and poured into heptane (120 mL). The resultingsuspension was filtered and the filter cake washed with heptane (40 mL).The filtrate was concentrated under reduced pressure and the resultingresidue was subjected to flash chromatography to afford 2 in 72% yield(10.7 g) as a clear oil: ¹H NMR (500 MHz, CDCl₃) δ 8.23 (d, 2H, J=9 Hz),7.74 (d, 2H, J=9.0 Hz), 5.40 (s, 1H), 3.82 (s, 3H); MS (ESI−) m/z 272(M−H). Reference: Tetrahedron 2002, 58, 10113.

1,4-Dimethyl-3-(4-nitrophenyl)piperazin-2-one (3)

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen, charged withN¹,N²-dimethylethane-1,2-diamine (1.61 g, 18.2 mmol), ethanol (5 mL) and2 (500 mg, 1.82 mmol), and the reaction was stirred at room temperaturefor 1 h. After this time, the reaction mixture was evaporated underreduced pressure, and the resulting residue was purified by flash columnchromatography to afford an 89% yield (404 mg) of 3 as a yellow oil: ¹HNMR (500 MHz, DMSO-d₆) δ 8.18 (d, 2H, J=8.5 Hz), 7.60 (d, 2H, J=8.5 Hz),3.87 (s, 1H), 3.61 (td, 1H, J=12.0, 4.0 Hz), 3.26 (ddd, 1H, J=12.0, 4.0,2.5 Hz), 3.02 (ddd, 1H, J=12.0, 4.0, 2.5 Hz), 2.84 (s, 3H), 2.64 (td,1H, J=12.0, 4.0 Hz), 2.06 (s, 3H).

3-(4-Aminophenyl)-1,4-dimethylpiperazin-2-one (4)

A 50-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 3 (200 mg, 0.80 mmol),ethanol (5 mL) and 10% palladium on carbon (50% wet, 4 mg dry weight).The reaction flask was purged with hydrogen gas and the reaction mixturestirred under a balloon pressure of hydrogen for 2 h. After this timethe flask was purged with nitrogen. The catalyst was removed byfiltration through a pad of Celite 521 and the filter cake washed withethanol (10 mL). The filtrate was concentrated under reduced pressure toafford a 94% yield of 4 (166 mg) as a colorless oil: ¹H NMR (500 MHz,DMSO-d₆) δ 6.89 (d, 2H, T=8.5 Hz), 6.47 (d, 2H, J=8.5 Hz), 4.94 (s, 2H),3.53 (td, 1H, J=12.0, 4.0 Hz), 3.44 (m, 1H), 3.21 (dt, 1H, J=12.0, 4.0Hz), 2.92 (dt, 1H, J=12.0, 4.0 Hz), 2.82 (s, 3H), 2.02 (s, 3H); MS(ESI+) m/z 220 (M+H).

5-Bromo-3-hydroxy-1-methyl-4H-pyrazin-2-one hydrogen bromide salt (5)

A 500-mL three-neck round bottomed flask equipped with a mechanicalstirrer and reflux condenser was purged with nitrogen and charged with2-(methylamino)acetonitrile (23.4 g, 220 mmol) and methylene chloride(200 mL). The suspension was treated with oxalyl bromide (50.0 g, 231mmol) and the reaction heated to reflux. After 2.5 days the resultingmixture was cooled to 0° C. and filtered. The filter cake was washedwith methylene chloride (2×30 mL) and dried to a constant weight undervacuum to afford a 79% yield of 5 (49.4 g) as an orange solid: mp161-162° C. dec; ¹H NMR (500 MHz, DMSO-d₆) δ12.00 (s, 1H), 5.11 (s, 1H),2.95 (s, 3H); MS (ESI+) m/z 205 (M−Br).

4,4,5,5-Tetramethyl-2-(2-methyl-3-nitro-phenyl)-[1,3,2]dioxaborolane (6)

A 1-L three-neck round-bottomed flask equipped with a mechanical stirrerand thermoregulator was purged with nitrogen and charged with2-bromo-6-nitrotoluene (60.2 g; 278 mmol), bis(pinacolato)diboron (85.2g; 336 mmol), potassium acetate (82.4 g; 840 mmol) and DMSO (320 mL). Astream of nitrogen was passed through the resulting suspension for 30min, [1,1′ bis(diphenylphosphino)-ferrocene]dichloropalladium (II),complex with dichloromethane (1:1) (7.60 g; 9.30 mmol) was then addedand the reaction heated at 85° C. for 20 h. After this time the mixturewas cooled to ambient temperature, poured into a mixture of water (1300mL) and MtBE (500 mL) and treated with Cellpure P65 (150 cc). Theresulting suspension was filtered through a pad of Cellpure P65 (200 cc)packed onto a fritted funnel (ID 185 mm). The filter cake was washedwith MtBE (3×180 mL) and the organic layer of the filtrate separated,washed with water (3×1 L) and dried over sodium sulfate. After filteringoff sodium sulfate, the filtrate was concentrated and purified by flashchromatography to afford4,4,5,5-tetramethyl-2-(2-methyl-3-nitro-phenyl)-[1,3,2]dioxaborolane (6)as a light yellow solid: mp 52-53° C.; MS (APCI+) m/z 264 (M+H).

2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(7)

A 500-mL round-bottomed flask equipped with a magnetic stirrer wascharged with4,4,5,5-Tetramethyl-2-(2-methyl-3-nitro-phenyl)-[1,3,2]dioxaborolane (6)(8.44 g; 32.1 mmol) and methanol (150 mL). The reaction flask was twiceevacuated and back-filled with argon. 10% Palladium on charcoal (50%wet, 425 mg dry weight) was then added to the solution, and the reactionflask evacuated and back-filled with hydrogen three times. The reactionwas then stirred under balloon pressure of hydrogen at room temperaturefor 13 h. After this time, the flask was twice evacuated and back-filledwith argon, then filtered through a pad of Celite 521 and the filtrateconcentrated in vacuo. The resulting residue was dried under high vacuumfor 1 d to afford a quantitative yield (8.16 g) of2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(7) as a white solid: nip 110-112° C.; MS (ESI+) m/z 234 (M+H).

4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carbonyl chloride (8)

4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid (1.0 g, 5.50mmol) is dissolved in dichloromethane [DCM] (25 mL) that contains 5drops of N,N-dimethylformamide dimethylformamide [DMF] under nitrogenand cooled to 0° C. Oxalyl chloride (13.7 mL of a 2.0M solution in ACM)is added via syringe and, allowed to warm to RT over 1 hour. All solventis then removed under reduced pressure, and the resultant oil is reducedfrom toluene (3×20 mL) to remove residual oxalyl chloride. The residueis then dissolved in ethyl acetate and washed with saturated sodiumbicarbonate (1×100 mL), then washed with saturated sodium chloride(1×100 mL) and dried over sodium sulfate. The solution is then filteredand concentrated under reduced pressure to give4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl chloride (8) as anoff-white solid (1.03 g).

4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide(9)

2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(7) (1.20 g, 5.16 mmol, 1.0 equiv) and pyridine (0.42 mL, 25.8 mmol) aredissolved in DCM (40 mL) at 0° C. under a nitrogen atmosphere.4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carbonyl chloride (8) (1.03 g,5.16 mmol) is then added in portions over 5 min and allowed to reactwarming to RT over 60 min. All solvent is then removed under reducedpressure, and the resultant oil is reduced from toluene (3×20 mL) toremove residual pyridine. The residue is then dissolved in ethyl acetateand washed with sodium hydroxide (1N, 1×100 mL), then washed withsaturated sodium chloride (1×100 mL) and dried over sodium sulfate. Thesolution is then filtered and concentrated under reduced pressure togive 4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]diaxaborolan-2-yl)-phenyl]-amide(9) as an off-white solid (1.87 g).

Sodium4-methyl-6-(2-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)phenyl)-3-oxo-3,4-dihydropyrazin-2-olate(10)

A 250-mL three-neck round-bottomed flask equipped with a mechanicalstirrer, reflux condenser and nitrogen inlet was charged with1,4-dioxane (100 mL) and aqueous 2.0 M sodium carbonate (15 mL, 29.5mmol). After bubbling nitrogen through the resulting solution for 15minutes, 5 (8.44 g, 29.5 mmol), 9 (12.9 g, 32.5 mmol) andtetrakis(triphenylphosphine)palladium (2.38 g, 2.06 mmol) were added andthe reaction mixture then heated at reflux for 20 h. After this time thereaction was cooled to room temperature and filtered through a pad ofCelite 521. The filter cake was washed with a 1:1 solution ofmethanol/methylene chloride (350 mL) and the filter cake discarded. Onstanding a precipitate formed in the filtrate and this solid wasfiltered. The filter cake was triturated with ethyl acetate (50 mL),filtered and dried under vacuum. The resulting solid was suspended inwater (75 mL), filtered and the filter cake washed with water (25 mL).The filter cake was dried to a constant weight to give a 53% yield (6.57g) of 10 as a light yellow solid: mp 225-230° C. dec, ¹H NMR (500 MHz,DMSO-d₆) δ 9.73 (s, 1H), 7.66 (s, 1H), 7.21 (m, 1H), 7.16 (m, 2H), 6.37(s, 1H), 2.75 (m, 2H), 2.61 (m, 2H), 2.20 (s, 3H), 1.77 (m, 4H); MS(ESI+) m/z 418 (M+H).

N-(3-(6-Bromo-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(11)

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with10 (6.55 g, 15.7 mmol) and anhydrous methylene chloride (60 mL). To theresulting suspension phosphorous oxybromide (9.95 g, 34.3 mmol) andN,N-dimethylformamide (190 mg, 2.60 mmol) were added and the reactionwas then heated at reflux for 4 h. After this time the reaction mixturewas poured into a 10% aqueous potassium carbonate solution (100 mL) andmethylene chloride (75 mL) was added. The resulting suspension wasfiltered through. Celite 521 and the layers separated. The aqueous layerwas extracted with methylene chloride (2×100 mL) and the combinedorganic layers were dried over sodium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was triturated with a 2:1solution of ethyl acetate/liexanes (10 mL) and filtered. The filter cakewas washed with the 2:1 ethyl acetate/hexanes solution (20 mL) and driedto a constant weight under vacuum to afford a 50% yield (3.59 g) of 11as a light yellow solid: nip 240-241° C., ¹H NMR (500 MHz, DMSO-d₆) δ9.86 (s, 1H), 7.98 (s, 1H), 7.67 (s, 1H), 7.28 (m, 3H), 3.57 (s, 3H),2.76 (t, 2H, J=5.5 Hz), 2.61 (t, 2H, J=5.5 Hz), 2.18 (s, 3H), 1.76 (m,4H); MS (ESI+) m/z 458 (M+H).

N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(12)

A 25-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 4 (160 mg, 0.73 mmol), 11(304 mg, 0.66 mmol), cesium carbonate (475 mg, 1.46 mmol) and1,4-dioxane (10 mL). After bubbling nitrogen through the resultingsolution for 30 minutes, Xantphos (32 mg, 0.056 mmol) andtris(dibenzylideneacetone)dipalladium(0) (30 mg, 0.033 mmol) were addedand the reaction mixture was heated at reflux for 16 h. After this timethe reaction was cooled to room temperature and concentrated underreduced pressure. The resulting residue was absorbed onto silica gel andpurified by flash chromatography to give a residue, which was furtherpurified by preparative reverse phase HPLC to afford a 30% yield (143mg) of 12 as a yellow solid: mp 155-156° C.;

¹H NMR (500 MHz, DMSO-d₆) δ 9.82 (s, 1H), 9.43 (s, 1H), 8.08 (d, 2H,J=7.5 Hz), 7.68 (s, 1H), 7.32 (d, 2H, J=7.5 Hz), 7.27-7.32 (m, 3H), 7.24(s, 1H), 4.88 (bs, 1H), 3.42-3.75 (m, 4H), 3.59 (s, 3H), 2.95 (s, 3H),2.76 (m, 2H), 2.61 (m, 5H), 2.28 (s, 3H), 1.78 (m, 4H); MS (ESI+) m/z597 (M+H).

EXAMPLE 2

3,5-dibromo-1-methyl-2(1H)pyrazinone (13)

(J. Heterocycl. Chem. 1983, 20, 919)

A 250-mL three-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 1,2-dichlorobenzene (1.00mL) and oxalyl bromide (60.6 g; 281 mmol). To the solution was addedmethylamino-acetonitrile (7.01 g; 65.8 mmol) and the reaction heatedunder nitrogen to 80° C. After 18 h the resulting mixture was cooled toroom temperature, evaporated under reduced pressure and the resultingresidue purified by flash chromatography to afford3,5-dibromo-1-methyl-2(1H)pyrazinone (13) (2.87 g, 16%) as an off-whitesolid: mp 94-95° C.; MS (ESI+) ink 267 (M+H).

5-Bromo-3-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-1-methylpyrazin-2(1H)-one(14)

A 100-mL three-neck round-bottomed flask equipped with a mechanicalstirrer and reflux condenser was charged with (4) (780 mg, 3.56 mmol),13 (998 mg, 3.73 mmol), cesium carbonate (2.36 g, 7.26 mmol) and1,4-dioxane (40 mL). After bubbling nitrogen through the resultingsolution for 30 minutes, Xantphos (0.162 g, 0.281 mmol) andtris(dibenzylideneacetone)dipalladium(0) (0.15 g, 0.165 mmol) wereadded, and the reaction mixture was heated at reflux for 16 h. Afterthis time the reaction was cooled to room temperature and concentratedunder reduced pressure. The resulting residue was absorbed onto silicagel and purified by flash chromatography to afford a 57% yield (818 mg)of 14 as an orange solid: nip 206-207° C.; ¹H NMR (500 MHz, CDCl₃) δ8.27 (bs, 1H), 7.72 (dd, 1H, J=2.0, 8.5 Hz), 7.36 (dd, 2H, J=2.0, 8.5Hz), 6.73 (s, 1H), 3.71 (m, 1H), 3.69 (s, 1H), 3.52 (s, 3H), 3.21 (m,1H), 3.01 (m, 1H), 2.97 (s, 3H), 2.67 (m, 1H), 2.19 (s, 3H); MS (ESI+)m/z 406 (M+H).

5-(3-Amino-2-methylphenyl)-3-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-1-methylpyrazin-2(1H)-one(15)

A 250-mL three-neck round-bottomed flask equipped with a magneticstirrer, reflux condenser and nitrogen inlet was charged with 14 (2.50g, 6.16 mmol), 7 (1.79 g, 7.70 mmol), 1,4-dioxane (70 mL) and a solutionof sodium carbonate (1.96 g, 18.5 mmol) in water (14 mL). After bubblingnitrogen through the resulting mixture for 30 min,tetrakis(triphenylphosphine)palladium (711 mg, 0.62 mmol) was added andthe reaction mixture then heated at reflux for 11 h. After this time thereaction was cooled to room temperature and 2N hydrochloric acid (70 mL)followed by ethyl acetate (70 mL) was added. The mixture was stirred for0.5 h and then filtered through a pad of Celite 521. The organic layerof the filtrate was separated and extracted with 2N hydrochloric acid(2×30 mL). The acidic extracts were combined and washed with ethylacetate (4×50 mL). The aqueous solution was then stirred vigorously withethyl acetate (100 mL) while solid potassium carbonate was addedportionwise until a pH of 12 was reached. The aqueous layer wasseparated and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with brine (70 mL) and dried over magnesiumsulfate. The drying agent was removed by filtration, and the filtratewas concentrated under reduced pressure and dried in a 49° C. vacuumoven for 24 h to afford 15 in 86% yield (2.32 g) as an amber foam: mp133-134° C.; ¹H NMR (500 MHz, CDCl₃)

8.29 (s, 1H), 7.80 (d, 1H, J=8.5 Hz), 7.29 (d, 2H, J=8.5 Hz), 7.05 (t,1H, J=8.0 Hz), 6.79 (d, 1H, J=7.5 Hz), 6.73 (d, 1H, J=7.5 Hz), 6.68 (s,1H), 3.72 (s, 3H), 3.64 (m, 1H), 3.20 (m, 1H), 3.01 (m, 1H), 2.99 (s,3H), 2.66 (m, 1H), 2.24 (s, 3H), 2.17 (s, 3H); MS (ESI+) m/z 433.3(M+H).

7-Oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic Acid (16)

A 25-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid (3.00 g, 16.5mmol), acetic acid (40 mL) and water (40 mL). A solution of ammoniumcerium(IV) nitrate (36.1 g, 65.9 mmol) in acetic acid (40 mL) was addeddropwise, and the reaction was stirred at room temperature for 1 h.After this time, the reaction mixture was poured into water (200 mL) andextracted with methylene chloride (3×200 mL). The organic extracts werecombined, dried over sodium sulfate, filtered and the solvent removedunder reduced pressure to afford 16 in 72% yield (2.35 g) as a yellowsolid: mp 174-175° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 13.60 (bs, 1H), 7.68(s, 1H), 2.86 (t, 2H, J=6.0 Hz), 2.59 (t, 2H, J=6.0 Hz), 2.08 (quintet,2H, J=6.0 Hz).

N-(3-(6(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(17)

A 50-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 15 (249 mg, 1.27mmol), 16 (500 mg, 1.16 mmol), N,N-diisopropylethylamine (600 mg, 4.64mmol) and anhydrous DMF (5 mL).Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP, 616 mg, 1.39 mmol) was added, and the reaction was stirred for 4h. After this time, the reaction was diluted with water (10 mL), and theresulting suspension was filtered. The filter cake was dissolved inmethylene chloride (20 mL), and the solution was washed with 10% aqueouscitric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), andwater (10 mL), and dried over sodium sulfate. The drying agent wasremoved by filtration, and the solvent was evaporated under reducedpressure. The resulting residue was purified by flash chromatography toafford a 52% yield of 17 (370 mg) as a white solid: mp 154-155° C.; ¹HNMR (500 MHz, CD₂Cl₂) δ 8.31 (s, 1H), 7.81 (dd, 1H, J=7.5, 1.5 Hz),7.76-7.72 (m, 3H), 7.50 (s, 1H), 7.28-7.23 (m, 4H), 6.73 (s, 1H), 3.64(td, 1H, J=11.5, 4.5 Hz), 3.57 (s, 1H), 3.55 (s, 3H), 3.14 (dt, 1H,J=11.5, 3.5 Hz), 2.93 (m, 1H), 2.88-2.86 (m, 5H), 2.62-2.57 (m, 3H),2.36 (s, 3H), 2.17 (m, 2H), 2.09 (s, 3H); MS (ESI+) m/z 611.2 (M+H).

N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-7-hydroxy-4,5,6,7-tetrahydrobenza[b]thiophene-2-carboxamide(18)

A 50-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 17 (250 mg, 0.409mmol) and methanol (10 mL). The resulting solution was cooled to 0° C.,and sodium borohydride (31 mg, 0.819 mmol) was added. After stirring thereaction at room temperature for 2 h, the solvent was evaporated underreduced pressure. The resulting residue was purified by flashchromatography to afford 18 in 88% yield (220 mg) as a white solid: mp165-166° C.; ¹H NMR (500 MHz, CD₂Cl₂) δ8.38 (s, 1H), 7.90 (d, 1H, J=7.5Hz), 7.81 (d, 2H, J=8.5 Hz), 7.71 (s, 1H), 7.39 (s, 1H), 7.34-7.27 (m,4H), 6.80 (s, 1H), 4.94 (m, 1H), 3.72 (td, 1H, J=11.5, 4.5 Hz), 3.65 (s,1H), 3.62 (s, 3H), 3.21 (m, 1H), 3.01 (m, 1H), 2.95 (s, 3H), 2.76-2.62(m, 3H), 2.43 (s, 3H), 2.22-2.13 (m, 5H), 2.02 (m, 1H), 1.83 (m, 2H); MS(ESI+) m/z 595.2 (M+H).

EXAMPLES 3A AND 3BN-(3-(6-(4-((2R)-1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(19)

N-(3-(6-(4-((2S)-1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-0)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(20)

The racemic mixture (12) was subjected to chiral separation onChiralcel-AD-H (60% isopropanol in heptane, with 0.1% trifluoroaceticacid) to give individual enantiomers at 4.6 minutes (20) ((−) isomer)([α]_(D) ²⁵=−37.8° (c=3.75, CHCl₃), mp=181-183° C.) and at 9.2 minutes(19) ((+) isomer) ([α]_(D) ²⁵=+38.8° (c=3.57, CHCl₃), mp=180-182° C.).Alternatively, the racemic mixture (12) was subjected to chiralseparation on Chiralpak AD (75% isopropanol in heptane, at 1 mL/min) andindividual enantiomers were collected from 17 to 27 minutes (20) ((−)isomer) and from 27 to 60 minutes (19) ((+) isomer).

Alternatively, racemic mixture (4) was subjected to separation onChiralpak AD (30% i-propanol/heptane 0.1% trifluoroacetic acid) to giveindividual enantiomers at 5.4 minutes (S-isomer) and 14.9 minutes(R-isomer). The individual isomers 19 and 20 were then prepared usingthe general synthetic routes described in Example 1 or Example 2.

5-Bromo-3-(4-((S)-1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-1-methylpyrazin-2(1H)-one((S)-14)

To a single-necked 250 mL round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged(−)-1,4-dimethyl-3-(4-aminophenyl)piperazin-2-one (8.2 g, 37.3 mmol),3,5-dibromo-1-methylpyrazin-2(1H)-one (10.0 g, 37.3 mmol), and i-PrOH(100 mL). Triethylamine (5.72 mL, 41 mmol, 1.1 eq) was then added andthe resulting suspension was heated at 80° C. for 16 hrs. A thick slurrywas observed the following day. The reaction was cooled to roomtemperature then concentrated in vacuo to −20 mL total volume. At thatpoint 20 mL of 2M Na₂CO₃ solution was added followed by 100 mL of water.The mixture was then allowed to slurry for 2 hrs at room temperature.The off-white solid was then collected on a fritted funnel and allowedto air dry for 1 hr. The solids were returned to the reaction flask and100 mL of diethyl ether/hexanes (1:1) was added and the suspension wastriturated at room temperature for 1 hr. The white solid was thencollected on a fritted funnel, dried on the filter with vacuum for 1 hr,then transferred to a round-bottomed flask and vacuum-dried overnight.White solids were obtained, 12.88 g (85%).

5-Bromo-3-(4-((R)-1,4-dimethyl-3-oxopiperazin-2yl)-phenylamino)-1-methylpyrazin-2(1H)-one((R)-14)

The (R)-isomer of compound 14 can be prepared from the (+)-isomer of1,4-dimethyl-3-(4-aminophenyl)piperazin-2-one using the same procedure.

EXAMPLE 4

tert-Butyl4-((1S,2S)-2,3-dihydroxy-1-isopropyl(methyl)amino)propyl)-phenylcarbamate(21)

A 50-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with D-(+) glyceraldehyde (90% purity, 1.62 g, 16.2mmol), ethanol (16 mL), N,N-methylisopropylamine (1.19 g, 16.3 mmol) and4-(tert-butoxycarbonylamino)-phenylboronic acid (3.85 g, 16.2 mmol). Theflask was sealed with a teflon stopper, and the reaction mixture wasstirred for 3 d. After this time the mixture was evaporated to drynessunder reduced pressure. The residue was dissolved in 10 mL of 2M aqueoussodium hydrogensulfate (20.0 mmol). The resulting solution was extractedwith methyl tent-butyl ether (2×150 mL), and the aqueous layer wasbasified by adding potassium carbonate (2.76 g, 20.0 mmol). Thesuspension was extracted with ether (2×50 mL), and the organic extractswere combined and dried over sodium sulfate. After removing the dryingagent by filtration, the solution was evaporated under reduced pressureto afford a 69% yield (3.79 g) of 21 as a white solid: mp 61-80° C.; ¹HNMR (300 MHz, DMSO-d₆) δ 9.23 (br s, 1H), 733 (d, 2H, J=8.4 Hz), 7.16(d, 2H, J=8.5 Hz), 4.58 (t, 1H, J=5.3 Hz), 4.22 (d, 1H, J=4.7 Hz), 3.96(quintet, 1H, J=5.4 Hz), 3.49 (d, 1H, J=6.2 Hz), 3.30 (m, 1H), 3.15 (m,1H), 2.83 (septet, 1H, J=6.5 Hz), 2.06 (s, 3H), 1.47 (s, 9H), 0.85 (d,3H, J=6.6 Hz), 0.79 (d, 3H, J=6.5 Hz); MS (ESI+) m/z 339 (M+H).

(S)-2-(4-(tart-Butoxycarbonylamino)phenyl)-2-(isopropyl(methyl)amino)aceticAcid (22)

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with 21 (1.01 g, 3.00 mmol), acetonitrile (6 mL),carbon tetrachloride (6 mL), water (9 mL) and ruthenium(III) chloridemonohydrate (39 mg, 0.17 mmol); and the resulting mixture was stirredfor 10 min. The reaction was cooled to −9° C., and sodium periodate(2.56 g, 12.0 mmol) was added. The mixture was slowly warmed to 0° C.over 1.5 h, and then stirred at 0° C. for 1 h and filtered. The filtercake was washed with ice-cold water (2×5 mL), and the filtrate wasdiluted with additional water (20 mL). The aqueous layer was separated,its acidity was adjusted to pH 5.8, and it was evaporated to dryness.The residue was triturated with water (10 mL) and the resultingsuspension was filtered. The filter cake was washed with water (2×1 mL)and methyl tent-butyl ether (2×5 mL), and dried overnight under reducedpressure to afford a 13% yield of 22 (121 mg) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 9.40 (s, 1H), 7.41 (d, 2H, J=8.8 Hz), 7.36 (d, 2H,J=8.8 Hz), 4.19 (s, 1H); 3.27 (septet, 1H, J=6.6 Hz), 2.21 (s, 3H), 1.47(s, 9H), 1.13 (d, 3H, J=6.6 Hz), 1.09 (d, 3H, J=6.6 Hz); MS (ESI+) m/z323 (M+H).

(S)-2-(4-Aminophenyl)-2-(isopropyl(methyl)amino)-N,N-dimethylacetamide(23)

A 25-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 22 (116 mg, 0.36mmol), 1-hydroxy-7-azabenzotriazole (50 mg, 0.37 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (208 mg,1.08 mmol) and DMF (2 mL), and the mixture was cooled to 0° C. A 2Msolution of dimethylamine in THF (0.3 mL, 0.6 mmol) was added, and thereaction was allowed to warm slowly to room temperature overnight. Asolution of potassium carbonate (2.00 g) in water (10 mL) was added, andthe mixture was extracted with hexanes (3×30 mL). The hexanes extractswere combined, dried over sodium sulfate, filtered, and evaporated todryness. The resulting crude product was mixed with methylene chloride(1 mL) and 4M solution of hydrogen chloride in dioxane (10 mL). Theresulting emulsion was vigorously stirred for 1 h at room temperature.After this time, the solvents were evaporated under reduced pressure,and the resulting residue was treated with water (2 mL) followed bypotassium carbonate (1.0 g), and then extracted with MtBE (10 mL). Theextract was evaporated and the residue was purified by flashchromatography on silica gel to afford a 58% yield (53 mg) of 23 as alight yellow oil: ¹H NMR (300 MHz, CDCl₃/CD₃OD) δ 7.20 (d, 2H, J=8.5Hz), 6.69 (d, 2H, J=8.5 Hz), 4.56 (s, 1H), 3.02 (s, 3H), 2.97 (m, 1H),2.91 (s, 3H), 2.11 (s, 3H), 1.03 (d, 3H, J=6.7 Hz), 1.00 (d, 3H, J=6.6Hz).

(S)-(+)-N-(3-(6-(4-(2-(Dimethylamino)-1-(isopropyl(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(24)

A 15-mL three-neck round-bottomed flask equipped with a magneticstirrer, nitrogen inlet and reflux condenser was charged with 23 (53 mg,0.212 mmol), 11 (98 mg, 0.212 mmol), cesium carbonate (152 mg, 0.468mmol) and 1,4-dioxane (3 mL). After bubbling nitrogen through theresulting solution for 30 minutes, Xantphos (10.4 mg, 0.018 mmol) andtris(dibenzylideneacetone)dipalladium(0) (9.70 mg, 0.010 mmol) wereadded and the reaction mixture was heated at reflux for 3 h. After thistime the reaction was cooled to room temperature, filtered and thefilter cake washed with methylene chloride (2×25 mL). The filtrate wasthen concentrated under reduced pressure and the residue was purified bycolumn chromatography to afford 24 (68 mg, 52%) as a yellow solid: mp133-134° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.79 (br s, 1H), 9.19 (br s,1H), 7.93 (d, 2H, J=8.5 Hz), 7.68 (s, 1H), 7.30 (m, 5H), 7.20 (s, 1H),4.56 (s, 1H), 3.55 (s, 3H), 3.01 (s, 3H), 2.84 (m, 1H), 2.76 (m, 5H),2.63 (t, 2H, J=5.5 Hz), 2.28 (s, 3H), 2.02 (s, 3H), 1.79 (m, 4H), 0.91(m, 6H); MS (ESI+) m/z 627.5 (M+H); [α]²⁵ _(D) +24.0° (c 0.25,chloroform).

EXAMPLE 5

2-[4-(tert-Butoxycarbonylamino)phenyl]-2-[isopropyl(methyl)amino]aceticAcid (25)

A 50-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with glyoxylic acid (618 mg, 6.72 mmol), toluene (20mL), N,N-isopropylmethylamine (486 mg, 6.60 mmol) and4-(tert-butoxycarbonylamino) phenylboronic acid (1.58 g, 6.66 mmol). Thereaction was sealed with a plastic cap under a nitrogen atmosphere andstirred at room temperature for 7 d. After this time, the reaction wasconcentrated under reduced pressure. The resulting residue was subjectedto flash chromatography to afford 25 in 62% yield (1.34 g) as a lightbrown solid: mp 320° C. dec, ¹H NMR (300 MHz, DMSO-d₆) δ 9.42 (s, 1H),7.42 (d, 2H, J=8.7 Hz), 7.37 (d, 2H, J=8.7 Hz), 4.23 (s, 1H), 3.28 (m,1H), 3.17 (s, 1H), 2.23 (s, 3H), 1.47 (s, 9H), 1.15 (d, 3H, f=6.6 Hz),1.11 (d, 3H, J=6.6 Hz); MS (ESI−) m/z 323 (M+H).

Ethyl2-[4-(tert-Butoxycarbonylamino)phenyl]-2-[isopropylmethyl)amino]acetate(26)

A 250-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 25 (1.50 g, 4.66mmol), THF (45 mL), 1-hydroxy-7-azabenzotriazole (1.27 g, 9.32 mmol) and1-ethyl-3-[3-dimethyl amino)propyl]-carbodiimide hydrochloride (1.79 g,9.32 mmol), and the reaction mixture was stirred for 15 min. Ethanol(429 mg, 9.32 mmol) and 4-dimethylamino pyridine (57 mg, 0.47 mmol) wereadded, and the reaction mixture was stirred at room temperature for afurther 16 h. After this time, the reaction was partitioned betweenwater (40 mL) and methylene chloride (50 mL). The layers were separated,and the aqueous phase was extracted with methylene chloride (2×30 mL).The organic extracts were combined and dried over sodium sulfate. Thedrying agent was removed by filtration, and the solvent was evaporatedunder reduced pressure. The resulting residue was dried to a constantweight under vacuum to afford 26 in 73% yield (1.20 g) as a white solid:mp 87-88° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.35 (s, 1H), 7.40 (d, 2H,J=7.5 Hz), 7.28 (d, 2H, J=7.5 Hz), 4.16 (s, 1H), 4.05 (m, 2H), 2.80(septet, 1H, J=6.5 Hz), 2.02 (s, 3H), 1.47 (s, 9H), 1.11 (t, 3H, J=7.0Hz), 0.94 (d, 3H, J=6.5 Hz), 0.88 (d, 3H, J=6.5 Hz); MS (ESI+) m/z 351(M−H).

Ethyl 2-(4-Aminophenyl)-2-[isopropyl(methyl)amino]acetate (27)

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with 26 (1.19 g, 3.40 mmol) and 4M hydrogen chloridein 1,4-dioxane (15.0 mL, 60 mmol), and the mixture was stirred at roomtemperature for 4 h. After this time, the reaction mixture wasconcentrated under reduced pressure, and the resulting residue waspartitioned between 10% aqueous potassium carbonate (100 mL) andmethylene chloride (75 mL). The layers were separated, and the aqueousphase was extracted with methylene chloride (2×75 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford 27 in 81% yield (878 mg)as an orange solid: mp 70-71° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 7.02 (d,2H, J=7.5 Hz), 6.49 (d, 2H, J=7.5 Hz), 5.07 (bs, 2H), 4.07-3.97 (m, 3H),2.81 (septet, 1H, J=6.5 Hz), 1.99 (s, 3H), 1.11 (t, 3H, J=7.0 Hz), 0.92(d, 3H, J=6.5 Hz), 0.85 (d, 3H, J=6.5 Hz); MS (ESI+) m/z 251 (M+H).

Ethyl2-(4-{6-[3-(4-tert-Butylbenzamido)-2-methylphenyl]-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino}phenyl)-2-[isopropyl(methyl)amino]acetate(28)

A 50-mL single-neck round-bottomed flask equipped with a magneticstirrer, nitrogen inlet and reflux condenser was charged with 27 (435mg, 1.74 mmol),4-tert-butyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl)-benzamide(717 mg, 1.58 mmol), cesium carbonate (1.13 g, 3.48 mmol) and1,4-dioxane (15 mL). After bubbling nitrogen through the resultingsolution for 20 minutes, Xantphos (78 mg, 0.134 mmol) andtris(dibenzylideneacetone) dipalladium(0) (72 mg, 0.079 mmol) wereadded, and the reaction mixture was heated at reflux for 16 h. Afterthis time, the reaction was cooled to room temperature, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography to afford a 43% yield (430 mg) of 28 as a yellowsolid: mp 119-120° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.88 (s, 1H), 9.24(s, 1H), 7.97 (d, 2H, J=8.5 Hz), 7.95 (d, 2H, J=8.5 Hz), 7.55 (d, 2H,J=8.5 Hz), 7.37 (dd, 1H, J=6.5, 3.5 Hz), 7.31 (d, 2H, J=8.5 Hz), 7.28(m, 2H), 7.22 (s, 1H), 4.18 (s, 1H), 4.04 (m, 2H), 3.56 (s, 3H), 2.81(septet, 1H, J=6.5 Hz), 2.29 (s, 3H), 2.02 (s, 3H), 1.33 (s, 9H), 1.11(t, 3H, J=7.0 Hz), 0.94 (d, 3H, J=6.5 Hz), 0.88 (d, 3H, J=6.5 Hz); MS(ESI+) m/z 624 (M+H).

2-(4-{6-[3-(4-tert-Butylbenzamido)-2-methylphenyl]-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino}phenyl)-2-[isopropyl(methyl)amino]aceticAcid (29)

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 28 (400 mg, 0.642 mmol),THF (5 mL) and ethanol (5 mL). A solution of lithium hydroxide (124 mg,10.2 mmol) in water (5 mL) was added, and the mixture was heated at 60°C. for 48 h. After this time, the reaction was cooled to roomtemperature, and the mixture was slowly acidified to pH 4.0 with 10%aqueous citric acid. The resulting precipitate was filtered, and thefilter cake was washed with water (20 mL), then triturated with a 1:10mixture of methylene chloride/ethyl acetate (20 mL). The resultingresidue was dried to a constant weight under vacuum at 45° C. to afford29 in 55% yield (210 mg) as an off-white solid: mp 197-198° C.; ³H NMR(500 MHz, DMSO-d₅) δ 9.91 (s, 1H), 9.29 (s, 1H), 7.99 (d, 2H, J=8.5 Hz),7.95 (d, 2H, J=8.5 Hz), 7.55 (d, 2H, J=8.5 Hz), 7.39 (d, 2H, J=8.5 Hz),7.35 (dd, 1H, J=7.0, 1.5 Hz), 7.32-7.28 (m, 2H), 7.24 (s, 1H), 4.23 (s,1H), 3.56 (s, 3H), 3.30 (m, 1H), 2.30 (s, 3H), 2.23 (s, 3H), 1.33 (s,9H), 1.13 (d, 3H, J=6.5 Hz), 1.10 (d, 3H, f=6.5 Hz); MS (ESI+) m/z 596(M+H).

4-tert-Butyl-N-(3-(6-(4-(1-(isopropyl(methyl)amino)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide(30)

To a sealed tube equipped with a magnetic stirrer, were charged 29 (100mg, 0.168 mmol), 1-methylpiperazine (14.6 mg, 0.168 mmol), DMF (3 mL),Hunig's base (65.1 mg, 0.503 mmol), and BOP (74.3 mg, 0.168 mmol). Thereaction mixture was stirred at room temperature for 26 hrs. Mostsolvent was removed by rotary evaporation and the resulting residue wasdissolved in ethyl acetate (100 mL). The solution was washed with water(15 mL×3), dried over MgSO₄, filtered and solvent removed in vacuo.Silica gel column chromatography (MeOH: CH₂Cl₂=5: 95) afforded 30 as alight yellow solid, 25 mg (22%). ¹H NMR (300 MHz, CDCl₃)

8.45 (s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 7.85 (m, 2H),7.75 (m, 1H), 7.54 (s, 1H), 7.51 (s, 1H), 7.40 (m, 2H), 7.19-7.23 (m,2H), 6.79 (s, 1H), 5.19 (s, 1H), 3.62 (s, 3H), 3.40 (broad s, 2H), 3.21(broad s, 2H), 2.26-2.50 (m, 9H), 2.18 (s, 3H), 1.92 (broad s, 2H), 1.34(s, 9H), 1.25-1.31 (m, 6H) ppm; MS (ESI+) m/z 678.19 (M+H).

EXAMPLE 6 3-(4-Nitrophenyl)-5,6-dihydropyrazin-2(1H)-one (31)

A 50-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen, charged with ethyl4-nitrophenylpyruvate (223 mg, 1.00 mmol), 3 pieces of molecular sieves(4-8 mesh, 3A) and anhydrous methanol (10 mL). The resulting solutionwas cooled to 0° C. with an ice bath and 1,2-ethylenediamine (63 mg,1.05 mmol) was added dropwise. After addition was complete the reactionwas stirred at room temperature for 1 h. After this time the resultingsuspension was filtered and the filter cake washed with cold methanol(2×5 mL). The filter cake was dried in an oven at 50° C. overnight undervacuum to afford 31 in 89% yield (196 mg) as a white solid: mp 191-192°C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.63 (bs, 1H), 8.26 (d, 2H, J=8.0 Hz),8.09 (d, 2H, J=8.0 Hz), 3.88 (t, 2H, J=6.5 Hz), 3.37 (m, 2H); MS (ESI+)m/z 220 (M+H).

4-Ethyl-3-(4-nitrophenyl)piperazin-2-one (32)

A 10-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen, charged with 31 (2.78 g, 12.7 mmol),acetaldehyde (727 mg, 16.5 mmol) and anhydrous methanol (40 mL). Asolution of sodium cyanoborohydride (2.4 g, 38 mmol) and anhydrous zincchloride (2.6 g, 19.1 mmol) in anhydrous methanol (40 mL) was added, andthe reaction was stirred at room temperature for 1 h. After this time,1N aqueous sodium hydroxide (25 mL) was added, and the methanol wasevaporated under reduced pressure. The remaining aqueous solution wasextracted with ethyl acetate (3×100 mL). The organic layers werecombined, washed: with water (100 mL) and brine (100 mL) and dried overmagnesium sulfate. The drying agent was, removed by filtration and thefiltrate concentrated under reduced pressure to afford a 98% yield (3.20g) of 32 as a yellow oil: ¹H NMR (500 MHz, DMSO-d₆) δ 8.18 (d, 2H, J=8.5Hz), 8.02 (d, 1H, J=4.0 Hz), 7.66 (d, 2H, J=8.5 Hz), 4.06 (s, 1H), 3.39(td, 1H, J=12.0, 4.0 Hz), 3.22 (m, 1H), 3.07 (dt, 1H, J=12.0, 3.0 Hz),2.50 (m, 1H), 2.37 (m, 1H), 2.21 (m, 1H), 0.91 (t, 3H, J=8.5 Hz); MS(ESI+) m/z 250 (M+H).

3-(4-Aminophenyl)-4-ethylpiperazin-2-one (33)

A 25-mL single-neck round-bottomed flask equipped with a refluxcondenser and magnetic stirrer was purged with nitrogen and charged with32 (210 ing, 0.89 mmol), ethanol (6 mL), iron powder (−325 mesh, 491 mg,8.93 mmol) and 2N hydrochloric acid (0.70 mL, 1.40 mind), and themixture was heated at reflux for 30 min. After this time, the reactionwas cooled to room temperature, and powdered potassium carbonate (3.03g, 22.0 mmol) was added. The resulting suspension was filtered and thefilter cake washed with ethanol (4×10 mL). The filtrate was concentratedunder reduced pressure to afford 33 in 100% yield (185 mg) as a whitesolid: mp 153-154° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.74 (d, 1H, J=2.7Hz), 6.90 (d, 2H, J=8.4 Hz), 6.47 (d, 2H, T=8.4 Hz), 4.95 (bs, 2H), 3.45(m, 1H), 3.42 (s, 1H), 3.14 (m, 1H), 2.89 (m, 1H), 2.44 (m, 1H), 2.02(s, 3H); MS (ESI+) m/z 206 (M+H).

5-Bromo-3-(4-(1-ethyl-3-oxopiperazin-2-yl)phenylamino]-ethylpyrazin-2(1H)-one(34)

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 33 (450 mg, 2.05 mmol),isopropanol (5 mL), 13 (603 mg, 2.26 mmol) and DL-10-camphorsulfonicacid (813 mg, 3.50 mmol), and the reaction mixture was then stirred atreflux for 16 h. After this time, the reaction mixture was cooled toroom temperature, filtered and the filter cake washed with isopropanol(10 mL). The resulting solid was dissolved in methylenechloride/methanol (3:1), absorbed onto silica gel and purified by flashchromatography to afford 34 in 79% yield (654 mg) as an orange solid:nip 152-153° C.; ¹H NMR (500 MHz, CDCl₃)

8.28 (bs, 1H7.73 (d, 2H, J=8.5 Hz), 7.43 (d, 2H, J=8.5 Hz), 6.74 (s,1H), 5.90 (d, 1H, J=3.5 Hz), 4.12 (s, 1H), 3.60 (m, 1H), 3.52 (s, 3H),3.36 (m, 1H), 3.12 (m, 1H), 2.60 (m, 2H), 2.28 (m, 1H), 1.00 (t, 3H,J=7.0 Hz); MS (ESI+) m/z 406.0 (M+H).

N-(3-(6-(4-(1-Ethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(35)

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer, reflux condenser and nitrogen inlet was charged with1,4-dioxane (13 mL), water (3 mL) and sodium carbonate (417 mg, 3.93mmol). After bubbling nitrogen through the resulting mixture for 15 min,34 (150 mg, 0.370 mmol),N-(6-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide. (192 mg, 0.460 mmol andtetrakis(triphenyl phosphine)palladium(0) (75 mg, 0.065 mmol) wereadded, and the reaction mixture then heated at reflux for 5 h. Afterthis time, the reaction mixture was cooled to room temperature, filteredand the filter cake washed with diethyl ether (10 mL). The resultingsolid was dissolved in methylene chloride/methanol (10:1), absorbed ontosilica gel and purified by flash chromatography to afford 35 in 41%yield (93 mg) as a yellow solid: mp 179-180° C.; ¹H NMR (500 MHz, CDCl₃)δ 8.31 (bs, 1H), 7.79 (d, 2H, J=8.5 Hz), 7.39 (m, 3H), 7.33 (m, 1H),7.22 (s, 1H), 7.04 (t, 1H, J=8.0 Hz), 6.68 (s, 1H), 5.80 (d, 1H, J=3.5Hz), 3.99 (s, 1H), 3.65 (s, 3H), 3.64 (m, 1H), 3.36 (m, 1H), 3.11 (m,1H), 2.82 (t, 2H, J=6.0 Hz), 2.66 (t, 2H, J=6.0 Hz), 2.59 (m, 2H), 2.36(s, 3H), 2.27 (m, 1H), 1.85 (m, 4H), 0.99 (t, 3H, J=7.0 Hz); MS (ESI+)m/z 615.3 (M+H).

EXAMPLE 7

2,6-Dibromopyridine-3-diazonium Tetrafluoroborate (36)

A 500-mL three-neck round-bottomed flask equipped with a magneticstirrer, nitrogen inlet and addition funnel was purged with nitrogen andcharged with 2,6-dibromo-3-aminopyridine (25.0 g, 99.2 mmol) and1,2-dimethoxyethane (70 mL), and the solution was cooled to −10° C.using an ice/acetone bath. A solution of boron trifluoride-diethyletherate (21.1 g, 148 mmol) in 70 mL of 1,2-dimethoxyethane was, addedat such a rate at to maintain the internal reaction temperature below−5° C.

After the addition was complete, a solution of tert-butyl nitrite (12.2g, 118 mmol) in 70 mL of 1,2-dimethoxyethane was added dropwisemaintaining the internal reaction temperature below −5° C. The reactionwas stirred for a further 1 h at −10° C. After this time the reactionwas filtered and the filter cake was washed with hexanes (3×75 mL) anddried at room temperature on air for 24 h, to afford a 98% yield (34.1g) of 36 as a white solid: mp 130-131° C.; ¹H NMR (300 MHz, DMSO-d₆)

7.72 (d, 1H, J=9.6 Hz), 5.66 (d, 1H, J=9.6 Hz).

2,6-Dibromo-3-fluoropyridine (37)

A 1-L single-neck round-bottomed flask equipped with a reflux condenseropen to air was charged with 36 (4.00 g, 11.4 mmol) which was equallydistributed on the flask bottom and placed in an oil bath at roomtemperature. The bath was heated to 80° C. over 20 min, then the bathtemperature was gradually increased to 130° C. over 30 min, until adecomposition occurred at an oil bath temperature of 130° C. Once all ofthe powder had visibly decomposed (the solid was transformed to a gooand the evolution of gas stopped), the reaction was cooled to roomtemperature and the resulting residue extracted with diethyl ether (3×75mL) decanting the ether extracts. The organic extracts were combined,washed with saturated aqueous sodium bicarbonate (200 mL) and dried oversodium sulfate. The drying agent was removed by filtration, and thefiltrate was concentrated under reduced pressure at room temperature toafford a 100% yield (3.00 g) of 37 as a yellow solid: mp 47-48° C.; ¹HNMR (300 MHz, CDCl₃) δ 7.44 (dd, 1H, J=3.3, 8.4 Hz), 7.31 (m, 1H).

N-(6-Bromo-3-fluoropyridin-2-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(38)

A 1-L three-neck round-bottomed flask equipped with a mechanicalstirrer, reflux condenser and nitrogen inlet was charged with1,4-dioxane (56 mL), 37 (3.00 g, 11.7mmol),4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (1.29 g, 7.12mmol) and cesium carbonate (5.09 g, 15.6 mmol). After bubbling nitrogenthrough the resulting solution for 30 min, Xantphos (350 mg, 0.605 mmol)and tris(dibenzylideneacetone)-dipalladium(0) (326 mg, 0.365 mmol) wereadded and the reaction mixture was heated at reflux for 2 h. After thistime the reaction was cooled to room temperature and filtered through, apad of Celite 521. The filter cake was washed with methylene chloride(50 mL). The filtrate was concentrated under reduced pressure and theresulting residue was purified by column chromatography using 500 cc ofsilica and eluting with 5% EtOAc/hexanes to afford a 37% yield of 38(940 mg) a white solid: R_(f)=0.55 (20% ethyl acetate in hexanes); ¹HNMR (500 MHz, CDCl₃) δ7.80 (bs, 1H), 7.38 (m, 1H), 7.37 (s, 1H), 7.32(dd, 1H, J=3.0, 8.0 Hz), 2.81 (t, 2H, J=6.5 Hz), 2.64 (t, 2H, J=6.0 Hz),1.85 (m, 4H); MS (ESI+) m/z 355.1 (M+H) andN-(6-bromo-5-fluoropyridin-2-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamidein 34% yield as a white solid: R_(f)=0.85 (20% ethyl acetate inhexanes);

¹H NMR (500 MHz, CDCl₃)

8.29 (dd, 1H, J=3.5, 9.0 Hz), 8.24 (bs, 1H), 7.47 (dd, 1H, m), 7.33 (s;1H), 2.81 (t, 2H, J=6.5 Hz), 2.64 (t, 2H, J=6.0 Hz), 1.85 (m, 4H); MS(ESI+) m/z 355.1 (M+H).

3-(4-(4-Ethyl-1-methyl-3-oxopiperazin-2-yl)phenylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2(1H)-one(39)

A 25 mL single-neck round-bottomed flask equipped with a magneticstirrer and thermoregulator was purged with nitrogen and charged with5-bromo-3-(4-(4-ethyl-1-methyl-3-oxopiperazin-2-yl)phenylamino)-1-methylpyrazin-2(1H)-one(225 mg, 0.536 mmol), bis(4,4,5,5-tetramethylpinacolato)diboron (170 mg,0.671 mmol) potassium acetate (210 mg, 2.06 mmol) and 1,4-dioxane (10mL). A stream of nitrogen was passed through the resulting suspensionfor 30 min. Pd(dppf)Cl₂.CH₂Cl₂ (15 mg, 0.016 mmol) was then added andthe reaction stirred at reflux for 3 h. After this time, the mixture wascooled to ambient temperature, partitioned between water (40 mL) andethyl acetate (60 mL) and filtered through a plug of Celite 521. Theorganic phase was separated, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was triturated withdiethyl ether (5 mL) and the suspension was filtered. The filter cakewas dried under vacuum at room temperature to afford) crude 39, whichwas used in the following reaction directly: MS (ESI+) m/z 468.2 (M+H).

N-(6-(6-(4-(4-Ethyl-1-methyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(40)

A 25-mL three-neck round-bottomed flask equipped with a magneticstirrer, reflux condenser and nitrogen inlet was charged with1,4-dioxane (7 mL), a solution of sodium carbonate (163 mg, 2.08 mmol)in water (1 mL), 38 (183 mg, 0.515 mmol) and 39 (0.537 mmol, presumingquantitative yield) After bubbling nitrogen through the resultingmixture for 30 min, tetrakis(triphenylphosphine)palladium(0) (60 mg,0.052 mmol) was added, and the reaction, mixture then heated at refluxfor 4 h. After this time, the reaction mixture was cooled to roomtemperature, and 2N hydrochloric acid (20 mL) followed by methylenechloride (20 mL) was added. The aqueous layer was separated, washed withmethylene chloride (2×25 mL) and then basified to pH 9 with saturatedaqueous potassium carbonate. The aqueous layer was then extracted withmethylene chloride (3×25 mL), and the organic extracts were combined anddried over sodium sulfate. The drying agent was removed by vacuumfiltration and the filtrate concentrated under reduced pressure toafford 40 in 30% yield (83 mg) as a yellow solid: mp 155-156° C.; ¹H NMR(500 MHz, CDCT₃) δ 8.27 (bs, 1H), 7.95 (dd, 1H, J=3.5, 8.5 Hz), 7.84 (m,3H), 7.72 (s, 1H), 7.55 (t, 1H, J=9.0 Hz), 7.46 (m, 3H), 4.01 (s, 1H),3.72 (m, 2H), 3.64 (s, 3H), 3.49 (m, 1H), 3.40 (m, 1H), 3.38 (m, 1H),3.24 (m, 1H), 2.83 (t, 2H, J=6.0 Hz), 2.67 (m, 3H), 1.86 (m, 4H), 1.16(t, 3H, J=7.5 Hz); MS (ESI+) m/z 616.3 (M+11).

EXAMPLE 8

5-Bromo-1-methyl-3-nitropyridin-2-one (41)

A 1-L round-bottomed flask equipped with a magnetic stirrer was purgedwith nitrogen and charged with 5-bromo-3-nitro-2-hydroxypyridine (24.0g, 0.11 mol), anhydrous DMF (280 mL) and powdered potassium carbonate(−350 mesh, 33.4 g, 0.24 mol), and the suspension stirred for 15 min atambient temperature. After this time methyl iodide (17.1 g, 0.124 mol)was added, and the mixture stirred at room temperature for 18 h. Thereaction mixture was then diluted with water (750 mL) and extracted withethyl acetate (3×1.0 L). The organic extracts were combined, washed withbrine (500 mL) and dried over sodium sulfate. After removing the dryingagent by filtration, the filtrate was evaporated to dryness underreduced pressure. The resulting residue was purified by flashchromatography on silica to afford an 85% yield (21.7 g) of 41 as ayellow solid: mp 122-423° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.37 (d, 1H,J=2.7 Hz), 7.26 (s, 1H), 3.68 (s, 3H); MS (ESI+) m/z 234 (M+H).

3-Amino-5-bromo-1-methylpyridin-2-one (42)

A 1-L three-neck round-bottomed flask equipped with a mechanical stirrerand reflux condenser was purged with nitrogen and charged with 41 (21.7g, 93.3 mmol), ethanol (305 mL), iron powder (−325 mesh, 52.1 g, 933mmol) and 2N hydrochloric acid (50 mL, 100 mmol), and the mixture washeated for 2 h at 60° C. After this time, the reaction was cooled toroom temperature, and potassium carbonate was added to pH 8 asdetermined by a pH paper. The resulting suspension was filtered and thefilter cake washed with ethanol (4×100 mL). The filtrate wasconcentrated under reduced pressure to yield a brown solid. This solidwas purified by column chromatography on silica gel to afford 42 in 77%yield (14.5 g) as an off-white powder: mp 104-105° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 7.15 (d, 1H, J=2.5 Hz), 6.46 (d, 1H, J=2.5 Hz), 5.45 (bs,2H), 3.40 (s, 3H); MS (ESI+) m/z 203 (M+H).

N-(3-(5-Amino-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-ethylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(43)

Using the same general procedure as described for the preparation of 10,42 (3.67 g) gave a 28% yield (2.10 g) of 43 as a yellow solid: mp210-211° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.78 (bs, 1H), 7.65 (s, 1H),7.25 (dd, 1H, J=1.5, 8.0 Hz), 7.21 (t, 1H, J=7.5 Hz), 7.09 (dd, 1H,J=1.0, 7.0 Hz), 6.89 (d, 1H, J=2.0 Hz), 6.43 (d, 1H, J=2.5 Hz), 5.19(bs, 2H), 3.49 (s, 3H), 2.75 (m, 2H), 2.62 (m, 2H), 2.12 (s, 3H), 1.77(m, 4H); MS (ESI+) m/z 394 (M+H).

N-[3-(5-{[5-(1,4-dimethyl-3-oxopiperazin-2-yl)pyridin-2-yl]amino}-1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide(44)

A 48-mL sealed tube equipped with a magnetic stirring bar was chargedwith 43 (0.20 g, 0.5 mmol),3-(6-chloropyridin-3-yl)-1,4-dimethylpiperazin-2-one (0.185 g, 0.8mmol), Pd₂(dba)₃ (0.032 g, 0.035 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.030 g, 0.05 mmol),and Cs₂CO₃ (0.326 g, 1.0 mmol) in dioxane (10 mL). After the mixture wasdegassed for 15 min., it was heated at 95° C. for 16 h. Then, thereaction mixture was cooled to room temperature and poured into H₂O (10mL). To this was added dichloromethane (10 mL) and the layers wereseparated. The aqueous phase was extracted with dichloromethane (3×10mL), and the combined organic extracts were washed with H₂O (5 mL) andbrine (5 mL), dried (Na₂SO₄), and concentrated. The crude mixture waspurified by column chromatography, gradient 0-10%, MeOH indichloromethane/ether (1/1), to afford 0.10 g (34%) of 44 as a solid; MS(ESI+) m/z 596 (M+H).

EXAMPLE 9

Ethyl2-(4-Ethylpiperazin-1-yl)-2-(4-(4-methyl-6-(2-methyl-3-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamido)phenyl)-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)acetate(45)

Using the same procedure as described for the preparation of 10, thereaction of ethyl2-(4-(6-Bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-2-(4-ethylpiperazin-1-yl)acetate(1.33 g) withN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide(1.26 g) gave a 73% yield (1.39 g) of 45 as a tan foam: mp 168-170° C.;¹H NMR (300 MHz, CDCl₃) δ 8.34 (s, 1H), 7.92 (d, 1H, J=7.8 Hz), 7.80 (d,2H, J=8.7 Hz), 7.54 (s, 1H), 7.39 (d, 2H, J=8.7 Hz), 7.39 (s, 1H), 7.27(t, 1H, J=8.1 Hz), 7.18 (dd, 1H, J=7.8, 1.2 Hz), 6.74 (s, 1H), 4.14 (m,2H), 3.91 (s, 1H), 3.60 (s, 3H), 2.87 (t, 2H, J=5.7 Hz), 2.76 (t, 2H,J=5.7 Hz), 2.61 (br s, 8H), 2.32 (s, 3H), 1.88 (m, 2H), 1.77 (m, 4H),1.17 (t, 3H, J=7.2 Hz), 1.05 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 683 (M+H).

2-(4-Ethylpiperazin-1-yl)-2-(4-(4-methyl-6-(2-methyl-3-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamido)phenyl)-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)aceticAcid (46)

Using the same procedure as described for the preparation of 29,saponification of 45 (1.29 g) gave a 97% yield (1.20 g) of 46 as anoff-white solid: mp 168-170° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 9.79 (s,1H), 9.25 (s, 1H), 7.96 (d, 2H, J=7.5 Hz), 7.70 (s, 1H), 7.29 (m, 6H),3.86 (m, 1H), 3.71 (s, 3H), 3.37 (q, 2H, J=7.2 Hz), 2.81 (m, 2H), 2.69(m, 2H), 2.42 s, 8H), 2.19 (s, 3H), 1.83 (br s, 2H), 1.61 (br s, 4H),0.95 (t, 3H, J=7.2 Hz); MS (ESI+), m/z 655 (M+H).

N-(3-(6-(4-(1-(4-Ethylpiperazin-1-yl)-2-((2-hydroxyethyl)(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide(47)

Using the same procedure as described for the preparation of 30, thereaction of 46 (307 mg) with 2-(methylamino)ethanol (71 mg) gave a 37%yield (125 mg) of 47 as a white solid: mp 163-165° C.; ¹H NMR (500 MHz,CDCl₃) δ 8.33 (s, 1H), 7.90 (d, 1H, J=8.0 Hz), 7.80 (d, 2H, J=9.0 Hz),7.62 (s, 1H), 7.48 (m, 1H), 7.41 (s, 1H), 7.35 (d, 2H, J=8.5 Hz), 7.27(t, 1H, J=8.0 Hz), 7.17 (d, 1H, J=7.5 Hz), 6.74 (s, 1H), 4.15 (s, 1H),3.72 (m, 2H), 3.62 (m, 1H), 3.61 (s, 3H), 3.50 (m, 2H), 3.02 (s, 3H),2.87 (t, 2H, J=5.5 Hz), 2.75 (t, 2H, J=−5.5 Hz), 2.56 (m, 8H), 2.40 (s,3H), 1.88 (m, 2H), 1.74 (m, 2H), 1.65 (m, 2H), 1.09 (t, 3H, J=7.0 Hz);MS (ESI+) m/z 712 (M+H).

EXAMPLE 10

The following compounds were prepared using procedures similar to thosedescribed in Examples 1-9.

MW MH+ Structure Name calc m/z obs

N-(3-(6-(4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-fluorophenyl)-4,5,6,7- tetrahydrobenzo[b]thiophene- 2-carboxamide 600.23601.3

N-(3-(6-(4-(1-(ethyl(isopropyl) amino)-2-((2-methoxyethyl)(methyl)amino)-2-oxoethyl) phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2- methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene- 2-carboxamide 684.35 685.0

N-(3-(6-(4-(1,2-bis(4-ethyl piperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo- 4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7- tetrahydrobenzo[b]thiophene- 2-carboxamide 736.39737.4

N-(3-(6-(4-(1,2-bis(4-ethyl piperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo- 4,5-dihydropyrazin-2-yl)-2-methylphenyl)-5,6,7,8- tetrahydro-4H-cyclo hepta[b]thiophene-2-carboxamide 750.40 751.4

N-(3-(6-(4-(1-ethyl-4-methyl- 3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetra hydrobenzo[b]thiophene-2- carboxamide 610.27611.5

4-tert-butyl-N-(3-(6-(4-(1- ethyl-4-methyl-3-oxopiperazin-2-yl)phenylamino)- 4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl) benzamide 606.33 607.3

(S)-N-(3-(6-(4-(3-(dimethyl amino)-2-(isopropyl(methyl)amino)-3-oxopropyl) phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2- methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene- 2-carboxamide 640.32 641.6

N-(3-(6-(4-(3-(dimethylamino)- 1-(isopropyl(methyl)amino)-3-oxopropyl)phenylamino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methyl phenyl)-4,5,6,7-tetrahydro benzo[b]thiophene-2-carboxamide 640.32 641.6

N-(3-(6-(4-(1-amino-2- morpholino-2- oxoethyl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2- methylphenyl)-4-tert-butylbenzamide 608.31 609.25

N-(3-(6-(4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetra hydrobenzo[b]thiophene-2- carboxamide 596.26597.2

4-tert-butyl-N-(3-(6-(4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide 592.32 593.3

N-(3-(6-(4-(2-amino-1- (isopropyl(methyl)amino)-2-oxoethyl)phenylamino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)- 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide 598.27 599.3

N-(2-methyl-3-(4-methyl-6-(4- (1-methyl-3-oxopiperazin-2-yl)phenylamino)-5-oxo-4,5- dihydropyrazin-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[b] thiophene-2-carboxamide 582.24 583.3

N-(3-(6-(4-(2-(dimethylamino)- 1-(isopropyl(methyl)amino)-2-oxoethyl)phenylamino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methyphenyl)- 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide 626.3 627.1

4-tert-butyl-N-(3-(6-(4-(2- (dimethylamino)-1-(isopropyl(methyl)amino)-2- oxoethyl)phenylamino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2- methylphenyl)benzamide 622.36 623.21

N-(3-(6-(4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2,5-difluorophenyl)-4,5,6,7- tetrahydrobenzo[b]thiophene- 2-carboxamide618.22 619.4

(S)-4-tert-butyl-N-(3-(6-(4- (1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl- 5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide 592.32 593.3

(R)-4-tert-butyl-N-(3-(6-(4- (1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl- 5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide 592.32 593.3

N-(3-(6-(4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenylamino)-5-oxo-4,5-dihydro pyrazin-2-yl)-2-methylphenyl)-4-(ethyl(methyl)amino) benzamide 579.30 580.2

(R)-N-(3-(6-(4-(2-(dimethyl amino)-1-(isopropyl(methyl)amino)-2-oxoethyl)phenyl amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2- methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene- 2-carboxamide 626.30 627.5

N-(3-(6-(4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl)-4-(1-ethyl cyclopropyl)benzamide 604.32 605.3

4-tert-butyl-N-(3-(6-(4-(1-(4- ethylpiperazin-1-yl)-2-morpholino-2-oxoethyl) phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2- methylphenyl)benzamide 705.40 706.30

N-(3-(6-(4-(1-(4-ethyl piperazin-1-yl)-2-morpholino-2-oxoethyl)phenylamino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)- 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide 709.34 710.3

N-(3-(6-(4-(1-(4-ethyl piperazin-1-yl)-2-morpholino-2-oxoethyl)phenylamino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methyl phenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2- carboxamide 732.36 724.3

N-(3-(6-(4-(1,2-bis(4-ethyl piperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo- 4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4-tert- butylbenzamide 732.45 733.5

4-tert-butyl-N-(3-(6-(4-(2- (dimethylamino)-1-(4-ethylpiperazin-1-yl)-2- oxoethyl)phenylamino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2- methylphenyl)benzamide 663.39 664.4

N-(3-(6-(4-(2-(dimethyl amino)-1-(4-ethylpiperazin-1-yl)-2-oxoethyl)phenylamino)- 4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7- tetrahydrobenzo[b]thiophene- 2-carboxamide 667.33668.4

N-(3-(6-(4-(2-(dimethyl amino)-1-(4-ethylpiperazin-1-yl)-2-oxoethyl)phenylamino)- 4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methyl phenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2- carboxamide 681.35 682.4

4-tert-butyl-N-(3-(6-(4-(1-(4- ethylpiperazin-1-yl)-2-((2-methoxyethyl)(methyl)amino)- 2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydro pyrazin-2-yl)-2-methylphenyl) benzamide 707.42708.4

N-(3-(6-(4-(1-(4-ethyl piperazin-1-yl)-2-((2- methoxyethyl)(methyl)amino)-2- oxoethyl)phenylamino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methyl phenyl)-4,5,6,7-tetrahydro benzo[b]thiophene-2-carboxamide 711.36 712.3

N-(3-(6-(4-(1-(4-ethyl piperazin-1-yl)-2-((2-methoxyethyl)(methyl)amino)-2- oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydro pyrazin-2-yl)-2-methylphenyl)-5,6,7,8-tetrahydro-4H- cyclohepta[b]thiophene-2- carboxamide 725.37726.3

N-(3-(6-(4-(1-isopropyl-4- methyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7- tetrahydrobenzo[b]thiophene- 2-carboxamide624.29 625.5

N-(3-(6-(4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl-amino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl)-5,6,7,8- tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide 610.27 610.9

N-(3-(6-(4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-5-fluoro-2-methylphenyl)-4,5,6,7- tetrahydrobenzo[b]thiophene- 2-carboxamide614.25 614.9

N-(2-chloro-3-(6-(4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,5,6,7- tetrahydrobenzo[b]thiophene- 2-carboxamide 616.20616.9

N-(3-(6-(4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl)-4-(ethyl (methyl)amino)benzamide 593.31 594.0

N-(3-(6-(4-(1-(ethyl(isopropyl) amino)-2-morpholino-2-oxoethyl)phenylamino)-4- methyl-5-oxo-4,5-dihydro pyrazin-2-yl)-2-methylphenyl)-4,5,6,7- tetrahydrobenzo[b]thiophene- 2-carboxamide 682.33683.3

N-(3-(6-(4-(1-(ethyl(isopropyl) amino)-2-(4-ethylpiperazin-1-yl)-2-oxoethyl)phenylamino)- 4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methyl phenyl)-4,5,6,7-tetrahydro benzo[b]thiophene-2-carboxamide 709.38 711.5

N-(3-(6-(4-(2-(dimethyl amino)-1-(ethyl(isopropyl)amino)-2-oxoethyl)phenyl mino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2- methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene- 2-carboxamide 640.32 641.3

N-{3-[6-({4-[2-(azetidin-1-yl)- 1-(morpholin-4-yl)-2-oxoethyl]phenyl}amino)-4- methyl-5-oxo-4,5-dihydro pyrazin-2-yl]-2-methylphenyl}-4,5,6,7-tetrahydro-1- benzothiophene-2- carboxamide 652.28 653.2

N-{2-methyl-3-[4-methyl-6- ({4-[(methylcarbamoyl)(morpholin-4-yl)methyl] phenyl}amino)-5-oxo-4,5-dihydropyrazin-2-yl]phenyl}- 4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide 626.27 627.2

N-{3-[6-({4-[2-(azetidin-1-yl)- 1-[ethyl(propan-2-yl)amino]-2-oxoethyl]phenyl}amino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}- 4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide 652.32 653.2

N-{3-[6-({4-[(dimethyl carbamoyl)[ethyl(propan-2-yl)amino]methyl]phenyl}amino)- 4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2- methylphenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2- carboxamide 654.86 655.6

N-{3-[6-({4-[1-(azetidin-1-yl)- 2-(4-ethylpiperazin-1-yl)-2-oxoethyl]phenyl}amino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methyl phenyl}-4H,5H,6H,7H,8H- cyclohepta[b]thiophene-2-carboxamide 693.35 694.3

N-[3-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl] amino}-5-oxo-4,5-dihydropyrazin-2-yl)-2- methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene- 2-carboxamide 582.24 583.0

N-{3-[6-({4-[azetidin-1- yl(dimethylcarbamoyl)methyl]phenyl}amino)-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H, 7H,8H-cyclohepta[b] thiophene-2-carboxamide624.29 625.4

N-[2-methyl-3-(4-methyl-5- oxo-6-{[4-(1,2,4-trimethyl-3-oxopiperazin-2-yl)phenyl] amino}-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro- 1-benzothiophene-2- carboxamide 610.27611.3

N-[5-chloro-3-(6-{[4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide634.19 635.6

N-{3-[6-({4-[azetidin-1- yl(dimethylcarbamoyl)methyl]phenyl}amino)-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4-tert- butylbenzamide 606.33 607.6

N-{3-[6-({4-[azetidin-1- yl(dimethylcarbamoyl)methyl]phenyl}amino)-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide610.27 611.5

N-(3-{6-[(4-{azetidin-1-yl[(2- hydroxyethyl)(methyl)- carbamoyl]methyl}-phenyl)amino]-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4,5,6,7- tetrahydro-1-benzothiophene-2-carboxamide 640.28 641.6

N-{2-methyl-3-[4-methyl-6- ({4-[4-methyl-3-oxo-1-(propan-2-yl)piperazin-2- yl]phenyl}amino)-5-oxo-4,5-dihydropyrazin-2-yl]phenyl}- 4H,5H,6H,7H,8H- cyclohepta[b]thiophene-2-carboxamide 638.3 639.7

N-{3-[6-({4-[(4-ethyl piperazin-1-yl)[(2-hydroxyethyl)(methyl)carbamoyl]methyl] phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]- 2-methylphenyl}-4H,5H,6H,7H,8H-cyclohepta[b] thiophene-2-carboxamide 711.36 712.4

N-{3-[6-({4-[(diethyl carbamoyl)(4-ethylpiperazin-1-yl)methyl]phenyl}amino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methyl phenyl}-4H,5H,6H,7H,8H- cyclohepta[b]thiophene-2-carboxamide 709.38 710.4

4-tert-butyl-N-(3-{6-[(4- {[ethyl(methyl)carbamoyl](4-ethylpiperazin-1-yl)methyl} phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}- 2-methylphenyl)benzamide 677.41 678.4

4-tert-butyl-N-{3-[6-({4- [(diethylcarbamoyl)(4-ethylpiperazin-1-yl)methyl] phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]- 2-methylphenyl}benzamide 691.42 692.4

N-[3-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl] amino)-5-oxo-4,5-dihydropyrazin-2-yl)-2- methylphenyl]-N-methyl- 4,5,6,7-tetrahydro-1-benzothiophene-2- carboxamide 596.26 597.0

4-tert-butyl-N-(2-methyl-3-{4- methyl-6-[(4-{1-[methyl(propan-2-yl)amino]-2- (morpholin-4-yl)-2-oxoethyl}phenyl)amino]-5-oxo-4,5- dihydropyrazin-2- yl}phenyl)benzamide 664.37665.1

N-{3-[6-({4-[2-(azetidin-1-yl)- 1-[methyl(propan-2-yl)amino]-2-oxoethyl]phenyl}amino)-4- methyl-5-oxo-4,5- dihydropyrazin-2-yl]-2-methylphenyl}-4-tert- butylbenzamide 634.36 635.1

N-{3-[6-({4-[1-(azetidin-1-yl)- 2-(morpholin-4-yl)-2-oxoethyl]phenyl}amino)-4- methyl-5-oxo-4,5- dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 652.28653.7

N-(3-{6-[(4-{azetidin-1-yl[(2- hydroxyethyl)(methyl)carbamoyl]methyl}phenyl)amino]-4- methyl-5-oxo-4,5- dihydropyrazin-2-yl}-2-methylphenyl)-4H,5H,6H,7H, 8H-cyclohepta[b]thiophene-2- carboxamide654.3 655.3

4-tert-butyl-N-(2-methyl-3-{4- methyl-6-[(4-{1-[methyl(propan-2-yl)amino]-2-(4- methylpiperazin-1-yl)-2-oxoethyl}phenyl)amino]-5- oxo-4,5-dihydropyrazin-2- yl}phenyl)benzamide677.41 678.2

N-(3-(6-(4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2- methylphenyl)-4-(1-methylcyclopropyl)benzamide 590.30 591.2

N-(3-(6-(4-(1-ethyl-4-methyl- 3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl)-5,6,7,8- tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide 624.29 625.7

4-tert-butyl-N-(3-(6-(4-(1- isopropyl-4-methyl-3-oxopiperazin-2-yl)phenyl amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2- methylphenyl)benzamide 620.35 621.7

N-[3-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl]-N-methyl- 4,5,6,7-tetrahydro- 1-benzothiophene-2-carboxamide 610 611.1

N-(3-{6-[(4-{1-[ethyl(methyl) amino]-2-(4-ethylpiperazin-1-yl)-2-oxoethyl}phenyl)amino]- 4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2- methylphenyl)-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2- carboxamide 695 696.4

N-[3-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl]-6-[ethyl (methyl)amino]pyridine-3- carboxamide 594 595.1

N-[3-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-fluoro-5-methylphenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 614615.3

N-{3-[6-({4-[2-(azetidin-1-yl)- 1-[methyl(propan-2-yl)amino]-2-oxoethyl]phenyl}amino)-4- methyl-5-oxo-4,5- dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,7H, 8H-cyclohepta[b]thiophene-2- carboxamide 652653

N-[3-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro-l- benzothiophene-2- carboxamide 582 583

N-[3-(6-{[4-(4-ethyl-1-methyl- 3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 610611.5

N-[3-(6-{[4-(4-ethyl-1-methyl- 3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl]-4H,5H,6H, 7H,8H-cyclohepta[b] thiophene-2-carboxamide 624625.3

N-[3-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2,5-dimethylphenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 610611.2

N-[5-chloro-3-(6-{[4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 630631.4

N-{3-[6-({4-[(dimethyl carbamoyl)(morpholin-4-yl)methyl]phenyl}amino)-4- methyl-5-oxo-4,5- dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 640640.9

N-{3-[6-({4-[(diethyl carbamoyl)(morpholin-4- yl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl]-2- methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene- 2-carboxamide 668 668.9

N-(3-{6-[(4-{[ethyl(methyl) carbamoyl](morpholin-4-yl)methyl}phenyl)amino]-4- methyl-5-oxo-4,5- dihydropyrazin-2-yl}-2-methylphenyl)-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 654654.9

N-(3-{6-[(4-{[(2-hydroxy ethyl)(methyl)carbamoyl](morpholin-4-yl)methyl}phenyl) amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2- methylphenyl)-4,5,6,7-tetrahydro-1-benzothiophene- 2-carboxamide 670 670.9

N-{3-[6-({4-[2-(3-hydroxy azetidin-1-yl)-1-(morpholin-4-yl)-2-oxoethyl]phenyl}amino)- 4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2- methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene- 2-carboxamide 668 669

N-{3-[6-({4-[(dimethyl carbamoyl)(morpholin-4-yl)methyl]phenyl}amino)-4- methyl-5-oxo-4,5- dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H, 7H,8H-cyclohepta[b]- thiophene-2-carboxamide 654654.9

N-{3-[6-({4-[(diethyl carbamoyl)(morpholin-4- yl)methyl]phenyl)amino)-4-methyl-5-oxo-4,5-dihydro pyrazin-2-yl]-2-methyl phenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2- carboxamide 682 683

N-{3-[6-({4-[2-(azetidin-1-yl)- 1-(morpholin-4-yl)-2-oxoethyl]phenyl}amino)-4- methyl-5-oxo-4,5-dihydro pyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,7H,8H- cyclohepta[b]thiophene-2- carboxamide 666 666.9

N-{2-methyl-3-[4-methyl-6- ({4-[(methylcarbamoyl)(morpholin-4-yl)methyl] phenyl}amino)-5-oxo-4,5-dihydropyrazin-2-yl]phenyl}- 4H,5H,6H,7H,8H- cyclohepta[b]thiophene-2-carboxamide 640 640.9

N-(3-{6-[(4-{[ethyl(methyl) carbamoyl](morpholin-4-yl)methyl}phenyl)amino]-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methyl phenyl)-4H,5H,6H,7H,8H- cyclohepta[b]thiophene-2-carboxamide 668 669

N-(3-{6-[(4-{[(2-hydroxy ethyl)(methyl)carbamoyl]-(morpholin-4-yl)methyl}phenyl) amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2- methylphenyl)-4H,5H,6H, 7H,8H-cyclohepta[b]thiophene-2-carboxamide 684 685

N-{3-[6-({4-[2-(3-hydroxy azetidin-1-yl)-1-(morpholin-4-yl)-2-oxoethyl]phenyl}amino)- 4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methyl phenyl}-4H,5H,6H,7H,8H- cyclohepta[b]thiophene-2-carboxamide 682 682.9

4-tert-butyl-N-[3-(6-{[4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-2- methoxybenzamide 622 623

N-[2-chloro-3-(6-{[4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-5-methylphenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 630631.5

N-[3-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2,6-dimethylphenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 610611.4

N-[3-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-5-methoxy-2-methylphenyl]- 4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide 626 627.3

N-[3-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2,6-difluorophenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 618619.2

N-[5-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 600601.3

N-[3-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 614615.3

N-[2,6-dichloro-3-(6-{[4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl]-5- oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro- 1-benzothiophene-2- carboxamide 650 651.4

N-[6-chloro-3-(6-{[4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 634635.2

N-[2-chloro-5-(6-{[4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro- 1-benzothiophene-2- carboxamide 616 617.2

N-[2-chloro-3-(6-{[4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-6-fluorophenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 634635.2

N-[2-cyano-5-(6-{[4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro- 1-benzothiophene-2- carboxamide 607 608.2

N-[4-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)-phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-6-fluoropyridin-2-yl]-4,5,6,7- tetrahydro-1-benzothiophene-2-carboxamide 601 602.2

4-tert-butyl-N-{3-[6-({4-[(S)- (dimethylcarbamoyl)[methyl-(propan-2-yl)amino]methyl] phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]- 2-methylphenyl}benzamide 622 623.4

4-tert-butyl-N-{3-[6-({4-[(R)- (dimethylcarbamoyl)(methyl-(propan-2-yl)amino]methyl] phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]- 2-methylphenyl}benzamide 622 623.4

4-tert-butyl-N-[3-(6-{[4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenyl]amino)-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-N-[3- (dimethylamino)propyl]- benzamide 677 678.4

N-[6-chloro-3-(6-{[4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 630631.3

N-[5-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)pyridin-3-yl]-4,5,6,7-tetrahydro-1- benzothiophene-2- carboxamide 583 584.2

N-[6-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)pyridin-2-yl]-4,5,6,7-tetrahydro-1- benzothiophene-2- carboxamide 583 584.2

N-[2-chloro-3-(6-{[4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-6-methylphenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 630631.3

N-[6-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-3-fluoropyridin-2-yl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide601 602.2

N-[6-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-5-fluoropyridin-2-yl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide601 602.2

N-[3-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl]-7-oxo-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide610 611.2

N-[3-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl]-7-hydroxy- 4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide 612 613.3

4-tert-butyl-N-[3-(6-{[4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-2- methylbenzamide 606 607.3

N-[3-(6-{[4-(1-ethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 614615.3

N-[3-(6-{[4-(1-ethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2,6-difluorophenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 618619.3

N-[3-(6-{(4-(1-ethyl-4-methyl- 3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2,6-difluorophenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 632633.3

N-[5-(6-{[4-(4-ethyl-1-methyl- 3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 614615.2

4-tert-butyl-N-[6-(6-{[4-(1,4- dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)pyridin-2-yl]benzamide 579 580.3

N-[5-(6-{[4-(1-ethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 600601.3

N-[5-(6-{[4-(1,4-diethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 628629.3

N-[3-(6-{[4-(4-ethyl-1-methyl- 3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2,6-difluorophenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 632633.3

N-[5-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-fluorophenyl]-7,7-difluoro- 4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide 636 637.3

N-[5-(6-{[4-(1-ethyl-4-methyl- 3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 614615.3

N-[6-(6-{[4-(1-ethyl-3- oxopiperazin-2- yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)- 3-fluoropyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene- 2-carboxamide 601 602.2

N-[6-(6-{[4-(4-ethyl-1-methyl- 3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl]-4,5,6,7- tetrahydro-1-benzothiophene-2-carboxamide 615 616.3

N-[6-(6-{[4-(1-ethyl-4-methyl- 3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl]-4,5,6,7- tetrahydro-1-benzothiophene-2-carboxamide 615 616.3

N-[6-(6-{[4-(1,4-diethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-3-fluoropyridin-2-yl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide629 630.3

N-[3-(6-{[4-(1,4-diethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 642643.3

N-[3-(6-{[4-(4-ethyl-1-methyl- 3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl]- 4,5,6,7-tetrahydro-l- benzothiophene-2-carboxamide 628 629.4

N-(5-[6-({4-[(2R)-1,4- dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl]-2-fluorophenyl}-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 600601.2

N-[3-(6-{[4-(1,4-diethyl-3- oxopiperazin-2- yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)- 2,6-difluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene- 2-carboxamide 646 647.3

N-{5-[6-({4-[(2S)-1,4- dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl]-2-fluorophenyl}-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 600601.5

N-{6-[6-({4-[(2S)-1,4- dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl]-3-fluoropyridin-2-yl}-4,5,6,7- tetrahydro-1-benzothiophene-2-carboxamide 601 602.3

N-{6-[6-({4-[(2R)-1,4- dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl]-3-fluoropyridin-2-yl}-4,5,6,7- tetrahydro-1-benzothiophene-2-carboxamide 601 602.2

N-[2-fluoro-5-(4-methyl-6-{[4- (4-methyl-3-oxopiperazin-2-yl)phenyl]amino}-5-oxo-4,5- dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro-1- benzothiophene-2- carboxamide 586 587.2

N-[3-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-2-fluoro-6-methylphenyl]- 4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide 614 615.3

N-[3-(6-{[4-(1-ethyl-4-methyl- 3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl]- 4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide 628 629.3

N-[5-(6-{[4-(2,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 600601.6

N-{5-[6-({4-[2-(azetidin-1-yl)- 1-(dimethylamino)-2-oxoethyl]phenyl}amino)-4- methyl-5-oxo-4,5- dihydropyrazin-2-yl]-2-fluorophenyl}-4,5,6,7- tetrahydro-1-benzothiophene- 2-carboxamide 614615.22

N-{2-fluoro-5-[6-({4-[1-(2- hydroxyethyl)-4-methyl-3- oxopiperazin-2-yl]phenyl}amino)-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl]phenyl}-4,5,6,7-tetrahydro- 1-benzothiophene-2- carboxamide 630 631.3

N-[5-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,4-difluoro- 4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide 636 637.3

N-[3-(6-{[4-(1,4-dimethyl-3- oxopiperazin-2-yl)phenyl]amino}-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-4-hydroxy- 4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide 612 613.3

N-[3-(5-{[5-(1,4-dimethyl- 3-oxopiperazin-2- yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6- dihydropyridin-3-yl)-2- methylphenyl]-4,5,6,7-tetrahydro-1- benzothiophene-2- carboxamide 596 597

EXAMPLE 11 Biochemical Btk Assay

A generalized procedure for one standard biochemical Btk Kinase Assaythat can be used to test compounds disclosed in this application is asfollows.

A master mix minus Btk enzyme is prepared containing 1× Cell Signalingkinase buffer (25 mM Tris-HCl, pH 7.5, 5 mM beta-glycerophosphate, 2 inM dithiothreitol, 0.1 mM Na₃VO₄, 10 mM MgCl₂), 0.5 μM Promega PTKBiotinylated peptide substrate 2, and 0.01% BSA. A master mix plus Btkenzyme is prepared containing 1× Cell Signaling kinase buffer, 0.5 μMPTK Biotinylated peptide substrate 2, 0.01% BSA, and 100 ng/well (0.06mU/well) Btk enzyme. Btk enzyme is prepared as follows: full lengthhuman wildtype Btk (accession number NM-000061) with a C-terminal V5 and6×His tag was subcloned into pFastBac vector for making baculoviruscarrying this epitope-tagged Btk. Generation of baculovirus is donebased on Invitrogen's instructions detailed in its published protocol“Bac-toBac Baculovirus Expression Systems” (Cat. Nos. 10359-016 and10608-016). Passage 3 virus is used to infect Sf9 cells to overexpressthe recombinant Btk protein. The Btk protein is then purified tohomogeneity using Ni-NTA column. The purity of the final proteinpreparation is greater than 95% based on the sensitive Sypro-Rubystaining. A solution of 200 μM ATP is prepared in water and adjusted topH7.4 with 1N NaOH. A quantity of 1.25 μL of compounds in 5% DMSO istransferred to a 96-well ½ area Costar polystyrene plate. Compounds aretested singly and with an 11-point dose-responsive curve (startingconcentration is 10 μM; 1:2 dilution). A quantity of 18.75 μL of mastermix minus enzyme (as a negative control) and master mix plus enzyme istransferred to appropriate wells in 96-well ½ area costar polystyreneplate. 5 μL of 200 μM ATP is added to that mixture in the 96-well ½ areaCostar polystyrene plate for final ATP concentration of 40 μM. Thereaction is allowed to incubate for 1 hour at room temperature. Thereaction is stopped with Perkin Elmer 1× detection buffer containing 30mM EDTA, 20 nM SA-APC, and 1 nM PT66 Ab. The plate is read usingtime-resolved fluorescence with a Perkin Elmer Envision using excitationfilter 330 nm, emission filter 665 nm, and 2^(nd) emission filter 615nm. IC₅₀ values are subsequently calculated. Alternatively, theLanthascreen assay can be used to evaluate Btk activity throughquantification of its phosphorylated peptide product. The FRET thatoccurs between the fluorescein on the peptide product and the terbium onthe detection antibody decreases with the addition of inhibitors of Btkthat reduce the phosphorylation of the peptide. In a final reactionvolume of 25 uL, Btk (h) (0.1 ng/25 ul reaction) is incubated with 50 mMHepes pH 7.5, 10 mM MgCl₂, 2 mM MnCl₂, 2 mM DTT, 0.2 mM NaVO4, 0.01%BSA, and 0.4 uM fluorescein poly-GAT. The reaction is initiated by theaddition of ATP to 25 uM (Km of ATP). After incubation for 60 minutes atroom temperature, the reaction is stopped by the addition of a finalconcentration of 2 nM Tb-PY20 detection antibody in 60 mM EDTA for 30minutes at room temperature. Detection is determined on a Perkin ElmerEnvision with 340 nM excitation and emission at 495 and 520 nm.

EXAMPLE 12 Ramos Cell Btk Assay

Another generalized procedure for a standard cellular Btk Kinase Assaythat can be used to test compounds disclosed in this application is asfollows.

Ramos cells are incubated at a density of 0.5×10⁷ cells/ml in thepresence of test compound for 1 hr at 37° C. Cells are then stimulatedby incubating with 10 μg/ml anti-human IgM F(ab)₂ for 5 minutes at 37°C. Cells are pelleted, lysed, and a protein assay is performed on thecleared lysate. Equal protein amounts of each sample are subject toSDS-PAGE and western blotting with either anti-phosphoBtk(Tyr223)antibody (Cell Signaling Technology #3531; Epitomics, cat. #2207-1) orphosphoBtk(Tyr551) antibody (BD Transduction Labs #558034) to assess Btkautophosphorylation or an anti-Btk antibody (ED Transduction Labs#611116) to control for total amounts of Btk in each lysate.

EXAMPLE 13 B-Cell Proliferation Assay

A generalized procedure for a standard cellular B-cell proliferationassay that can be used to test compounds disclosed in this applicationis as follows.

B-cells are purified from spleens of 8-16 week old Balb/c mice using aB-cell isolation kit (Miltenyi Biotech, Cat # 130-090-862). Testingcompounds are diluted in 0.25% DMSO and incubated with 2.5×10⁵ purifiedmouse splenic B-cells for 30 min prior to addition of 10 μg/ml of ananti-mouse IgM antibody (Southern Biotechnology Associates Cat #1022-01) in a final volume of 100 μl. Following 24 hr incubation, 1μCi³H-thymidine is added and plates are incubated an additional 36 hrprior to harvest using the manufacturer's protocol for SPA[³H] thymidineuptake assay system (Amersham Biosciences # RPNQ 0130). SPA-bead basedfluorescence is counted in a microbeta counter (Wallace Triplex 1450,Perkin Elmer).

EXAMPLE 14 T Cell Proliferation Assay

A generalized procedure for a standard T cell proliferation assay thatcan be used to test compounds disclosed in this application is asfollows.

T cells are purified from spleens of 8-16 week old Balb/c mice using aPan T cell isolation kit (Miltenyi Biotech, Cat # 130-090-861). Testingcompounds are diluted in 0.25% DMSO and incubated with 2.5×10⁵ purifiedmouse splenic T cells in a final volume of 100 n1 in flat clear bottomplates precoated for 90 min at 37° C. with 10 μg/ml each of anti-CD3 (BD# 553057) and anti-CD28 (BD # 553294) antibodies. Following 24 hrincubation, 1 μCi ³H-thymidine is added and plates incubated anadditional 36 hr prior to harvest using the manufacturer's protocol forSPA[³H] thymidine uptake assay system (Amersham Biosciences # RPNQ0130). SPA-bead based fluorescence was counted in a microbeta counter(Wallace Triplex 1450, Perkin Elmer).

EXAMPLE 15 CD86 Inhibition Assay

A generalized procedure for a standard assay for the inhibition of Bcell activity that can be used to test compounds disclosed in thisapplication is as follows.

Total mouse splenocytes are purified from spleens of 8-16 week oldBalb/c mice by red blood cell lysis (BD Pharmingen #555899). Testingcompounds are diluted to 0.5% DMSO and incubated with 1.25×10⁶splenocytes in a final volume of 200 μl in flat clear bottom plates(Falcon 353072) for 60 min at 37° C. Cells are then stimulated with theaddition of 15 μg/ml IgM (Jackson ImmunoResearch 115-006-020), andincubated for 24 hr at 37° C., 5% CO₂. Following the 24 hr incubation,cells are transferred to conical bottom clear 96-well plates andpelleted by centrifugation at 1200×g×5 min. Cells are preblocked byCD16/CD32 (BD Pharmingen #553142), followed by triple staining withCD19-FITC (BD Pharmingen #553785), CD86-PE (BD Pharmingen #553692), and7AAD (BD Pharmingen #51-68981E). Cells are sorted on a BD FACSCaliburand gated on the CD19⁺/7AAD⁻ population. The levels of CD86 surfaceexpression on the gated population is measured versus test compoundconcentration.

EXAMPLE 1 B-ALL Cell Survival Assay

The following is a procedure for a standard B-ALL cell survival studyusing an XTT readout to measure the number of viable cells. This assaycan be used to test compounds disclosed in this application for theirability to inhibit the survival of B-ALL cells in culture. One humanB-cell acute lymphoblastic leukemia line that can be used is SUP-B15, ahuman Pre-B-cell ALL line that is available from the ATCC.

SUP-B15 pre-B-ALL cells are plated in multiple 96-well microtiter platesin 100 μl of Iscove's media+20% FBS at a concentration of 5×10⁵cells/ml. Test compounds are then added with a final conc. of 0.4% DMSO.Cells are incubated at 37° C. with 5% CO₂ for up to 3 days. After 3 dayscells are split 1:3 into fresh 96-well plates containing the testcompound and allowed to grow up to an additional 3 days. After each 24 hperiod, 50 ul of an XTT solution (Roche) is added to one of thereplicate 96-well plates and absorbance readings are taken at 2, 4 and20 hours following manufacturer's directions. The reading taken with anOD for DMSO only treated cells within the linear range of the assay(0.5-1.5) is then taken and the percentage of viable cells in thecompound treated wells are measured versus the DMSO only treated cells.

EXAMPLE 17

The compounds disclosed in the examples above were tested in the Btkbiochemical assay described herein (Example 11) and all of thosecompounds of Formula I disclosed in the examples above exhibited an IC₅₀value less than or equal to 2 micromolar and certain of those compoundsexhibited an IC₅₀ value less than or equal to 1 micromolar. Certain ofthose compounds exhibited an IC₅₀ value less than or equal to 25 nM.Certain of those compounds exhibited an IC₅₀ value less than or equal to5 nM.

Some of the compounds disclosed in the examples above were tested in theB-cell proliferation assay (as described in Example 13) and exhibited anIC₅₀ value less than or equal to 10 micromolar. Certain of thosecompounds exhibited an IC₅₀ value less than or equal to 500 nM. Certainof those compounds exhibited an IC₅₀ value less than or equal to 50 nMin this assay.

Certain compounds disclosed herein exhibited IC₅₀ values for inhibitionof T-cell proliferation that were at least 3-fold, and in some instances10-fold, or even 100-fold greater than the IC₅₀ values of thosecompounds for inhibition of B-cell proliferation.

Some of the compounds disclosed herein were tested in an assay forinhibition of B cell activity (under the conditions described in Example15), and exhibited an IC₅₀ value less than or equal to 10 micromolar.Certain of those compounds exhibited an IC₅₀ value less than or equal to0.5 micromolar. Certain of those compounds exhibited an IC₅₀ value lessthan or equal to 100 nM in this assay.

Some of the compounds disclosed herein were tested in a B-cell leukemiacell survival assay (under the conditions described in Example 16), andexhibit an IC₅₀ value less than or equal to 10 micromolar.

Some of the compounds disclosed herein exhibited both biochemical andcell-based activity. For example, some of the compounds disclosed hereinexhibited an IC₅₀ value less than or equal to 1 micromolar in the Btkbiochemical assay described herein (Example 11) and an IC₅₀ value lessthan or equal to 10 micromolar in at least one of the cell-based assays(other than the T-cell assay) described herein (Examples 12, 13, 15 or16). Certain of those compounds exhibited an IC₅₀ value less than orequal to 50 nM in the Btk biochemical assay described herein (Example11) and an IC₅₀ value less than or equal to 500 nM in at least one ofthe cell-based assays (other than the T-cell assay) described herein(Examples 12, 13, 15 or 16). Certain of those compounds exhibited anIC₅₀ value less than or equal to 10 nM and an IC₅₀ value less than orequal to 100 nM in at least one of the cell-based assays (other than theT-cell assay) described herein (Examples 12, 13, 15 or 16).

While some embodiments have been shown and described, variousmodifications and substitutions may be made thereto without departingfrom the spirit and scope of the invention. For example, for claimconstruction purposes, it is not intended that the claims set forthhereinafter be construed in any way narrower than the literal languagethereof, and it is thus not intended that exemplary embodiments from thespecification be read into the claims. Accordingly, it is to beunderstood that the present invention has been described by way ofillustration and not limitations on the scope of the claims.

1. A method for treating a patient having a disease chosen from cancer,bone disorders, autoimmune diseases, inflammatory diseases, acuteinflammatory reactions, and allergic disorders comprising administeringto the patient an effective amount of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof, or a mixturethereof, wherein

X is chosen from N and CR²; Y is chosen from N and CR^(3′); Z is chosenfrom N and CR³; provided that only one of X, Y and Z is N; W is N; V isCH; R¹ is chosen from:

R² is chosen from H, CH₃, F, Cl, CN, OCH₃, OH and CF₃; R^(2′) is chosenfrom H and F; R³ is chosen from H, CH₃, CF₃, F, Cl, CN and OCH₃; R^(3′)is chosen from H, CH₃, F, Cl, CN and OCH₃; R⁴ is

m is chosen from 0 and 1; n is chosen from 0 and 1; R⁵ is chosen from H,C₁-C₆ alkyl, and C₃-C₆ cycloalkyl, wherein said alkyl is optionallysubstituted with one or more substituents chosen from OH, F, and OCH₃;R⁶ is chosen from H and C₁-C₆ alkyl; or R⁵ and R⁶ are optionally takentogether with the nitrogen atom to which they are attached to form a 4-to 6-membered cyclic ring having 0-1 additional N, S or O, wherein theoptional additional ring nitrogen is optionally substituted with C₁-C₃alkyl and said cyclic ring is optionally substituted with OH; R⁷ ischosen from H, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl, wherein said alkyl isoptionally substituted with one or more substituents chosen from OH andO(C₁-C₄ alkyl); or R⁶ and R⁷ are optionally taken together with the—N(R⁵)C(R⁹)(CH₂)_(n)C(═O)N(R⁸)— group through the respective nitrogenatoms to which they are directly attached to form a 6-membered cyclicring; R⁸ is chosen from H and C₁-C₆ alkyl, wherein said alkyl isoptionally substituted with one or more substituents chosen from OH, F,and OCH₃; or R⁷ and R⁸ are optionally taken together with the nitrogenatom to which they are attached to form a 4- to 6-membered cyclic ringhaving 0-1 additional N, S or O, wherein the optional additional ringnitrogen is optionally substituted with C₁-C₃ alkyl and said cyclic ringis optionally substituted with OH; R⁹ is chosen from H and CH₃; R¹⁰ ischosen from OH, H and C₁-C₃ alkyl optionally substituted with N(R⁹)₂;R¹¹ is chosen from H, CH₃ and CF₃; and R¹² is C₁-C₃ alkyl.
 2. The methodof claim 1, wherein R¹¹ is CH₃.
 3. The method of claim 2, wherein W is Nand V is CH.
 4. The method of claim 3, wherein X is CR².
 5. The methodof claim 3, wherein X is N.
 6. The method of claim 3, wherein Y isCR^(3′).
 7. The method of claim 3, wherein Y is N.
 8. The method ofclaim 3, wherein Z is CR³.
 9. The method of claim 3, wherein Z is N. 10.The method of claim 3, wherein the compound is:


11. The method of claim 1, wherein R^(2′) is F.
 12. The method of claim1, wherein R^(2′) is H.
 13. The method of claim 12, wherein R¹ is chosenfrom:

R² is chosen from H, CH₃, F, and Cl; R³ is chosen from H, CH₃, F, andCl; R^(3′) is chosen from H, CH₃, F and Cl; R⁵ is chosen from H andC₁-C₆ alkyl; R⁶ is chosen from H and C₁-C₆ alkyl; or R⁵ and R⁶ areoptionally taken together with the nitrogen atom to which they areattached to form a 6-membered cyclic ring having 0-1 additional N, S orO, wherein the optional additional ring nitrogen is optionallysubstituted with C₁-C₃ alkyl; R⁸ is chosen from H and C₁-C₆ alkyl; or R⁷and R⁸ are optionally taken together with the nitrogen atom to whichthey are attached to form a 4- to 6-membered cyclic ring having 0-1additional N, S or O, wherein the optional additional ring nitrogen isoptionally substituted with C₁-C₃ alkyl; R¹⁰ is chosen from H or C₁-C₃alkyl; and R¹¹ is CH₃. 14-35. (canceled)
 36. The method of claim 1,wherein said compound is selected from:N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(4-(1-(Ethyl(isopropyl)amino)-2-((2-methoxyethyl)(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(4-(1,2-Bis(4-ethylpiperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(4-(1,2-Bis(4-ethylpiperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide;N-(3-(6-(4-(1-Ethyl-4-methyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;4-tert-Butyl-N-(3-(6-(4-(1-ethyl-4-methyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;(S)-N-(3-(6-(4-(3-(Dimethylamino)-2-(isopropyl(methyl)amino)-3-oxopropyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(4-(3-(Dimethylamino)-1-(isopropyl(methyl)amino)-3-oxopropyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydro benzo[b]thiophene-2-carboxamide;N-(3-(6-(4-(1-Amino-2-morpholino-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4-tert-butylbenzamide;N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;4-tert-Butyl-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;N-(3-(6-(4-(2-Amino-1-(isopropyl(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-Methyl-3-(4-methyl-6-(4-(1-methyl-3-oxopiperazin-2-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(4-(2-(Dimethylamino)-1-(isopropyl(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methyphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;4-tert-Butyl-N-(3-(6-(4-(2-(dimethylamino)-1-(isopropyl(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,5-difluorophenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;(S)-4-tert-Butyl-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;(R)-4-tert-Butyl-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4-(ethyl(methyl)amino)benzamide;(R)-N-(3-(6-(4-(2-(Dimethylamino)-1-(isopropyl(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4-(1-ethylcyclopropyl)benzamide;4-tert-Butyl-N-(3-(6-(4-(1-(4-ethylpiperazin-1-yl)-2-morpholino-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;N-(3-(6-(4-(1-(4-Ethylpiperazin-1-yl)-2-morpholino-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(4-(1-(4-ethylpiperazin-1-yl)-2-morpholino-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide;N-(3-(6-(4-(1,2-Bis(4-ethylpiperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4-tert-butylbenzamide;4-tert-Butyl-N-(3-(6-(4-(2-(dimethylamino)-1-(4-ethylpiperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;N-(3-(6-(4-(2-(Dimethylamino)-1-(4-ethylpiperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(4-(2-(Dimethylamino)-1-(4-ethylpiperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide;4-tert-Butyl-N-(3-(6-(4-(1-(4-ethylpiperazin-1-yl)-2-((2-methoxyethyl)(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;N-(3-(6-(4-(1-(4-Ethylpiperazin-1-yl)-2-((2-methoxyethyl)(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(4-(1-(4-Ethylpiperazin-1-yl)-2-((2-methoxyethyl)(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide;N-(3-(6-(4-(1-Isopropyl-4-methyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide;N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-5-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-Chloro-3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4-(ethyl(methyl)amino)benzamide;N-(3-(6-(4-(1-(Ethyl(isopropyl)amino)-2-morpholino-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(4-(1-(Ethyl(isopropyl)amino)-2-(4-ethylpiperazin-1-yl)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(4-(2-(Dimethylamino)-1-(ethyl(isopropyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-{3-[6-({4-[2-(Azetidin-1-yl)-1-(morpholin-4-yl)-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{2-Methyl-3-[4-methyl-6-({4-[(methylcarbamoyl)(morpholin-4-yl)methyl]phenyl}amino)-5-oxo-4,5-dihydropyrazin-2-yl]phenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{3-[6-({4-[2-(Azetidin-1-yl)-1-[ethyl(propan-2-yl)amino]-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{3-[6-({4-[(Dimethylcarbamoyl)[ethyl(propan-2-yl)amino]methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;N-{3-[6-({4-[1-(azetidin-1-yl)-2-(4-ethylpiperazin-1-yl)-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methyl phenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;N-[3-(6-{[4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{3-[6-({4-[Azetidin-1-yl(dimethylcarbamoyl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;N-[2-Methyl-3-(4-methyl-5-oxo-6-{[4-(1,2,4-trimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[5-Chloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{3-[6-({4-[Azetidin-1-yl(dimethylcarbamoyl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4-tert-butylbenzamide;N-{3-[6-({4-[Azetidin-1-yl(dimethylcarbamoyl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-(3-{6-[(4-{Azetidin-1-yl[(2-hydroxyethyl)(methyl)carbamoyl]methyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{2-Methyl-3-[4-methyl-6-({4-[4-methyl-3-oxo-1-(propan-2-yl)piperazin-2-yl]phenyl}amino)-5-oxo-4,5-dihydropyrazin-2-yl]phenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;N-{3-[6-({4-[(4-Ethyl piperazin-1-yl)[(2-hydroxyethyl)(methyl)carbamoyl]methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide; N-{3-[6-({4-[(Diethylcarbamoyl)(4-ethylpiperazin-1-yl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;4-tert-Butyl-N-(3-{6-[(4-{[ethyl(methyl)carbamoyl](4-ethylpiperazin-1-yl)methyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)benzamide;4-tert-Butyl-N-{3-[6-({4-[(diethylcarbamoyl)(4-ethylpiperazin-1-yl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}benzamide;N-[3-(6-{[4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-N-methyl-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[(4-{1-[methyl(propan-2-yl)amino]-2-(morpholin-4-yl)-2-oxoethyl}phenyl)amino]-5-oxo-4,5-dihydropyrazin-2-yl}phenyl)benzamide;N-{3-[6-({4-[2-(Azetidin-1-yl)-1-[methyl(propan-2-yl)amino]-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4-tert-butylbenzamide;N-{3-[6-({4-[1-(Azetidin-1-yl)-2-(morpholin-4-yl)-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-(3-{6-[(4-{Azetidin-1-yl[(2-hydroxyethyl)(methyl)carbamoyl]methyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;4-tert-Butyl-N-(2-methyl-3-{4-methyl-6-[(4-{1-[methyl(propan-2-yl)amino]-2-(4-methylpiperazin-1-yl)-2-oxoethyl}phenyl)amino]-5-oxo-4,5-dihydropyrazin-2-yl}phenyl)benzamide;N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4-(1-methylcyclopropyl)benzamide;N-(3-(6-(4-(1-Ethyl-4-methyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-2-carboxamide;4-tert-Butyl-N-(3-(6-(4-(1-isopropyl-4-methyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)benzamide;N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;(S)-N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;(R)-N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;and(S)-(+)-N-(3-(6-(4-(2-(Dimethylamino)-1-(isopropyl(methyl)amino)-2-oxoethyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-N-methyl-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-(3-{6-[(4-{1-[ethyl(methyl)amino]-2-(4-ethylpiperazin-1-yl)-2-oxoethyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-6-[ethyl(methyl)amino]pyridine-3-carboxamide;N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluoro-5-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{3-[6-({4-[2-(azetidin-1-yl)-1-[methyl(propan-2-yl)amino]-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(4-ethyl-1-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(4-ethyl-1-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,5-dimethylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[5-chloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{3-[6-({4-[(dimethylcarbamoyl)(morpholin-4-yl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{3-[6-({4-[(diethylcarbamoyl)(morpholin-4-yl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-(3-{6-[(4-{[ethyl(methyl)carbamoyl](morpholin-4-yl)methyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-(3-{6-[(4-{[(2-hydroxyethyl)(methyl)carbamoyl](morpholin-4-yl)methyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{3-[6-({4-[2-(3-hydroxyazetidin-1-yl)-1-(morpholin-4-yl)-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{3-[6-({4-[(dimethylcarbamoyl)(morpholin-4-yl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;N-{3-[6-({4-[(diethylcarbamoyl)(morpholin-4-yl)methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;N-{3-[6-({4-[2-(azetidin-1-yl)-1-(morpholin-4-yl)-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;N-{2-methyl-3-[4-methyl-6-({4-[(methylcarbamoyl)(morpholin-4-yl)methyl]phenyl}amino)-5-oxo-4,5-dihydropyrazin-2-yl]phenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;N-(3-{6-[(4-{[ethyl(methyl)carbamoyl](morpholin-4-yl)methyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;N-(3-{6-[(4-{[(2-hydroxyethyl)(methyl)carbamoyl](morpholin-4-yl)methyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;N-{3-[6-({4-[2-(3-hydroxyazetidin-1-yl)-1-(morpholin-4-yl)-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4H,5H,6H,7H,8H-cyclohepta[b]thiophene-2-carboxamide;4-tert-butyl-N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-2-methoxybenzamide;N-[2-chloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-5-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-dimethylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-5-methoxy-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-difluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[5-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[2,6-dichloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[6-chloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[2-chloro-5-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[2-chloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[2-cyano-5-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[4-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoropyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;4-tert-butyl-N-{3-[6-({4-[(S)-(dimethylcarbamoyl)[methyl(propan-2-yl)amino]methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}benzamide;4-tert-butyl-N-{3-[6-({4-[(R)-(dimethylcarbamoyl)[methyl(propan-2-yl)amino]methyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}benzamide;4-tert-butyl-N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-N-[3-(dimethylamino)propyl]benzamide;N-[6-chloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[5-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-3-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[6-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[2-chloro-3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[6-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[6-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-5-fluoropyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-7-oxo-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-7-hydroxy-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;4-tert-butyl-N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-2-methylbenzamide;N-[3-(6-{[4-(1-ethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(1-ethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-difluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(1-ethyl-4-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-difluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[5-(6-{[4-(4-ethyl-1-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;4-tert-butyl-N-[6-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2-yl]benzamide;N-[5-(6-{[4-(1-ethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[5-(6-{[4-(1,4-diethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(4-ethyl-1-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-difluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[5-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-7,7-difluoro-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[5-(6-{[4-(1-ethyl-4-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[6-(6-{[4-(1-ethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[6-(6-{[4-(4-ethyl-1-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[6-(6-{[4-(1-ethyl-4-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[6-(6-{[4-(1,4-diethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(1,4-diethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(4-ethyl-1-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{5-[6-({4-[(2R)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-fluorophenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(1,4-diethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-difluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{5-[6-({4-[(2S)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-fluorophenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{6-[6-({4-[(2S)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-fluoropyridin-2-yl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{6-[6-({4-[(2R)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-3-fluoropyridin-2-yl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[2-fluoro-5-(4-methyl-6-{[4-(4-methyl-3-oxopiperazin-2-yl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluoro-6-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(1-ethyl-4-methyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[5-(6-{[4-(2,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{5-[6-({4-[2-(azetidin-1-yl)-1-(dimethylamino)-2-oxoethyl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-fluorophenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{2-fluoro-5-[6-({4-[1-(2-hydroxyethyl)-4-methyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]phenyl}-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[5-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl]-4,4-difluoro-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl]-4-hydroxy-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;andN-[3-(5-{[5-(1,4-dimethyl-3-oxopiperazin-2-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide.37. (canceled)
 38. (canceled)
 39. (canceled)
 40. (canceled) 41.(canceled)
 42. (canceled)
 43. (canceled)
 44. (canceled)
 45. (canceled)46. The method of claim 1, wherein said disease is cancer.
 47. Themethod of claim 1, wherein said disease is B-cell lymphoma or leukemia.48. The method of claim 1, wherein an effective amount of said compoundis administered intravenously, intramuscularly, or parenterally.
 49. Themethod of claim 1, wherein an effective amount of said compound isadministered orally.
 50. A method of claim 1, wherein said disease is anautoimmune disease an acute inflammatory reaction, or an allergicdisorder selected from systemic lupus erythematosus, rheumatoidarthritis, multiple vasculitides, idiopathic thrombocytopenic purpura,myasthenia gravis, allergic rhinitis, and asthma. 51-62. (canceled) 63.The method of claim 1, further comprising administering to the patientan effective amount of a second active agent.
 64. A method of claim 1,wherein said compound is of Formula IX:

wherein R¹ is chosen from:

R² is H, CH₃, F, or Cl; R³ is H, CH₃, F, or Cl; R^(3′) is H, CH₃, F, orCl; R⁴ is

m is 0 or 1; n is 0 or 1; R⁵ is H or C₁-C₆ alkyl; R⁶ is H or C₁-C₆alkyl; or R⁵ and R⁶ are optionally taken together with the nitrogen atomto which they are attached to form a 6-membered cyclic ring having 0-1additional N, S or O, wherein the optional additional ring nitrogen isoptionally substituted with C₁-C₃ alkyl; R⁷ is H or C₁-C₆ alkyl, whereinsaid alkyl is optionally substituted with one or more substituentschosen from OH and O(C₁-C₄ alkyl); or R⁶ and R⁷ are optionally takentogether with the —N(R⁵)C(R⁹)(CH₂)_(n)C(═O)N(R⁸)— group through therespective nitrogen atoms to which they are directly attached to form a6-membered cyclic ring; R⁸ is H or C₁-C₆ alkyl; or R⁷ and R⁸ areoptionally taken together with the nitrogen atom to which they areattached to form a 4- to 6-membered cyclic ring having 0-1 additional N,S or O, wherein the optional additional ring nitrogen is optionallysubstituted with C₁-C₃ alkyl; R⁹ is H or CH₃; and R¹⁰ is H or C₁-C₃alkyl.
 65. The method of claim 36, wherein said compound isN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide.66. The method of claim 36, wherein said compound is(R)-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide.67. The method of claim 36, wherein said compound isN-[3-(6-{[4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl]amino}-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluoro-6-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide.